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University of Utah
1.
Huang, Xiaosong.
Distinct Roles of Cellular Copper and Erythropoietin Receptor on Hematopoietic Engraftment.
Degree: PhD, Pathology;, 2010, University of Utah
URL: http://content.lib.utah.edu/cdm/singleitem/collection/etd2/id/1204/rec/355
► Cell differentiation is influenced by a combination of cues from both extracellular and intracellular sources. Recent advances in the regulation of hematopoiesis have focused on…
(more)
▼ Cell differentiation is influenced by a combination of cues from both extracellular and intracellular sources. Recent advances in the regulation of hematopoiesis have focused on the roles of the growth factors, cytokines, transcription factors and microRNAs; little attention has been given to the role of cellular metabolism. In the first part of this dissertation, I explored the idea that an essential cellular nutrient, copper (Cu), is an active component of cell fate regulators that influence hematopoietic progenitor cell differentiation. I showed that reducing cellular Cu content by exposing the cells to the Cu chelator tetraethylenepentamine (TEPA) enhanced the generation or maintenance of erythroid progenitor cells from multipotent progenitor cells in culture. I also provided evidence suggesting that this effect is likely due to the modulation of cellular energy metabolism by cell Cu level. In the second part of this dissertation, I investigated the effects of modulating erythropoietin receptor (EPOR) signaling intensity on mouse trilineage hematopoietic engraftment and proliferation of hematopoietic stem/progenitor cells (HSC/HPCs). I showed that neither increasing nor reducing EpoR signaling intensity influence long-term leukocyte engraftment, an indication of HSC function. I confirmed the essential role of EpoR on erythropoiesis. I also provide evidence suggesting a potential role for EpoR in megakaryopoiesis. I also demonstrated that multipotent progenitor cells with naturally-expressed hyperactive EpoR can proliferate and differentiate in response to Epo stimulation alone.
Subjects/Keywords: Hematopoiesis; Copper
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APA (6th Edition):
Huang, X. (2010). Distinct Roles of Cellular Copper and Erythropoietin Receptor on Hematopoietic Engraftment. (Doctoral Dissertation). University of Utah. Retrieved from http://content.lib.utah.edu/cdm/singleitem/collection/etd2/id/1204/rec/355
Chicago Manual of Style (16th Edition):
Huang, Xiaosong. “Distinct Roles of Cellular Copper and Erythropoietin Receptor on Hematopoietic Engraftment.” 2010. Doctoral Dissertation, University of Utah. Accessed March 04, 2021.
http://content.lib.utah.edu/cdm/singleitem/collection/etd2/id/1204/rec/355.
MLA Handbook (7th Edition):
Huang, Xiaosong. “Distinct Roles of Cellular Copper and Erythropoietin Receptor on Hematopoietic Engraftment.” 2010. Web. 04 Mar 2021.
Vancouver:
Huang X. Distinct Roles of Cellular Copper and Erythropoietin Receptor on Hematopoietic Engraftment. [Internet] [Doctoral dissertation]. University of Utah; 2010. [cited 2021 Mar 04].
Available from: http://content.lib.utah.edu/cdm/singleitem/collection/etd2/id/1204/rec/355.
Council of Science Editors:
Huang X. Distinct Roles of Cellular Copper and Erythropoietin Receptor on Hematopoietic Engraftment. [Doctoral Dissertation]. University of Utah; 2010. Available from: http://content.lib.utah.edu/cdm/singleitem/collection/etd2/id/1204/rec/355
2.
Lim, Yiting.
Translating insights from normal, neoplastic hematopoiesis and myeloid disease progression into potential clinical applications.
Degree: 2014, Johns Hopkins University
URL: http://jhir.library.jhu.edu/handle/1774.2/37983
► Certain cancers, especially those occurring in the hematopoietic system, can be identified by their cell of origin, and share many similar properties and signaling pathways…
(more)
▼ Certain cancers, especially those occurring in the hematopoietic system, can be identified by their cell of origin, and share many similar properties and signaling pathways to their normal counterparts. We use the hematopoietic system to interrogate the relationship between normal and neoplastic transformation. This work aims to better understand the molecular mechanisms of disease transformation in hematologic malignancies and translate basic biology findings into potential clinical applications. To examine how normal
hematopoiesis is perturbed, we investigated how low dose-rate radiation affected hematopoietic cells in a whole animal model, and uncover mechanisms to mitigate this adverse effect. Although the effects of acute radiation exposure have been well studied for many years, it is likely that widespread life-threatening radiation incidents will occur in the form of lethal doses delivered at relatively low rates over protracted time periods. We show that damage
to hematopoietic progenitors and hematopoietic failure is a consequence of such radiation exposure. In addition, the anti-malaria agent chloroquine can protect these hematopoietic progenitors by activating ATM, a key player in the DNA damage response pathway, thus enhancing overall survival. We provide a mechanistic explanation and potentially viable prophylaxic therapy for protracted low dose-rate radiation induced death. The Hedgehog signaling pathway is highly conserved and important for development. Though its role in normal
hematopoiesis is controversial, it does not impact normal adult
hematopoiesis. Hedgehog signaling is aberrantly regulated in many cancers, including several hematopoietic malignancies. We found Hedgehog signaling to be upregulated in human secondary leukemias. We hypothesize that Hedgehog signaling plays a role in disease progression and generated a novel transgenic mouse model of myeloid disease progression. Conditional activation of Hedgehog signaling
dramatically accelerated disease progression from a chronic myeloproliferative disorder initiated by an activating mutation in the FLT3 tyrosine kinase receptor to rapidly fatal acute myeloid leukemia. Mice harboring both the FLT3-ITD (a commonly found mutation in adult AML) and SmoM2, (a constitutively active form of Smoothened) alleles died rapidly from AML caused by increased myeloid progenitor proliferation. Pharmacologically inhibiting both Hedgehog and FLT3 pathways synergistically reduced leukemic growth and improved overall survival compared to targeting either pathway alone.
Advisors/Committee Members: Small, Donald (advisor).
Subjects/Keywords: Hematopoiesis;
leukemia
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APA (6th Edition):
Lim, Y. (2014). Translating insights from normal, neoplastic hematopoiesis and myeloid disease progression into potential clinical applications. (Thesis). Johns Hopkins University. Retrieved from http://jhir.library.jhu.edu/handle/1774.2/37983
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lim, Yiting. “Translating insights from normal, neoplastic hematopoiesis and myeloid disease progression into potential clinical applications.” 2014. Thesis, Johns Hopkins University. Accessed March 04, 2021.
http://jhir.library.jhu.edu/handle/1774.2/37983.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lim, Yiting. “Translating insights from normal, neoplastic hematopoiesis and myeloid disease progression into potential clinical applications.” 2014. Web. 04 Mar 2021.
Vancouver:
Lim Y. Translating insights from normal, neoplastic hematopoiesis and myeloid disease progression into potential clinical applications. [Internet] [Thesis]. Johns Hopkins University; 2014. [cited 2021 Mar 04].
Available from: http://jhir.library.jhu.edu/handle/1774.2/37983.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lim Y. Translating insights from normal, neoplastic hematopoiesis and myeloid disease progression into potential clinical applications. [Thesis]. Johns Hopkins University; 2014. Available from: http://jhir.library.jhu.edu/handle/1774.2/37983
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Toronto
3.
Notta, Faiyaz.
Clonal Analysis of Normal and Malignant Human Hematopoietic Hierarchies.
Degree: 2011, University of Toronto
URL: http://hdl.handle.net/1807/31884
► The overall aim of my thesis is to gain insight into the cellular and molecular basis of the hierarchical organization of the human blood system,…
(more)
▼ The overall aim of my thesis is to gain insight into the cellular and molecular basis of the hierarchical organization of the human blood system, and how these normal development processes are subverted into leukemogenesis. To date, the major cellular classes that comprise human blood remain ill defined as rigorous clonal analysis required to define the self-renewal and lineage potential of single cells has not yet been performed. Here, identification CD49f as a novel marker of human HSC led to the ability to transplant single human HSC in NOD-scid IL2Rgc-/- mice. Loss of CD49f and Thy1 uniquely demarcated multi-potent progenitors (MPP) from HSC.
The classical model of hematopoiesis posits the segregation of lymphoid and myeloid lineages as the earliest fate decision during lineage restriction from HSC. The validity of this model in the mouse has been questioned; however, little is known about the lineage potential of human progenitors. By clonally mapping the developmental potential of seven progenitor classes from neonatal cord blood and adult bone marrow, human multi-lymphoid progenitors (MLP) were identified as a distinct population of Thy1-/loCD45RA+ cells in the CD34+CD38- stem cell compartment that can give rise to all lymphoid cell types, as well as monocytes, macrophages and dendritic cells. This indicates that these myeloid lineages arise in early lymphoid lineage specification. Thus, as in the mouse, human hematopoiesis does not follow a rigid model of myeloid-lymphoid segregation.
While non-genetic mechanisms govern cell-fate commitment and lineage specification, hematopoietic malignancies are often initiated by aberrant gene rearrangements that can subvert normal cellular processes. Full transformation requires the accumulation of multiple genetic lesions. Most tumours exhibit dramatic genetic heterogeneity downstream of the initiating oncogenic event and are composed of pockets of genetically distinct clonal subpopulations. However little is known of how diversity evolves or the impact diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, it was demonstrated that genetic diversity occurs in functionally defined leukaemia-initiating cells (L-IC) and that many diagnostic patient samples contain multiple genetically distinct L-IC subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, while in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A/B, and a trend to poor patient outcome. Our findings link clonal diversity with L-IC function and underscore the importance of developing therapies that eradicate all intratumoural subclones.
PhD
Advisors/Committee Members: Dick, John E., Molecular and Medical Genetics.
Subjects/Keywords: hematopoiesis; leukemia; 0306
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Notta, F. (2011). Clonal Analysis of Normal and Malignant Human Hematopoietic Hierarchies. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/31884
Chicago Manual of Style (16th Edition):
Notta, Faiyaz. “Clonal Analysis of Normal and Malignant Human Hematopoietic Hierarchies.” 2011. Doctoral Dissertation, University of Toronto. Accessed March 04, 2021.
http://hdl.handle.net/1807/31884.
MLA Handbook (7th Edition):
Notta, Faiyaz. “Clonal Analysis of Normal and Malignant Human Hematopoietic Hierarchies.” 2011. Web. 04 Mar 2021.
Vancouver:
Notta F. Clonal Analysis of Normal and Malignant Human Hematopoietic Hierarchies. [Internet] [Doctoral dissertation]. University of Toronto; 2011. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1807/31884.
Council of Science Editors:
Notta F. Clonal Analysis of Normal and Malignant Human Hematopoietic Hierarchies. [Doctoral Dissertation]. University of Toronto; 2011. Available from: http://hdl.handle.net/1807/31884

Universiteit Utrecht
4.
Lange, T.A.D.
The role of Cdx in embryonic and adult mammalian hematopoiesis.
Degree: 2011, Universiteit Utrecht
URL: http://dspace.library.uu.nl:8080/handle/1874/209132
► All blood cells orginate from a common stem cell in the bone marrow: the hematopoietic stem cell (HSC), which is characterized by two main properties:…
(more)
▼ All blood cells orginate from a common stem cell in the bone marrow: the hematopoietic stem cell (HSC), which is characterized by two main properties: self-renewal and multipotency.
Hematopoiesis is a hierarchical system with the HSC at the top. During embryogenesis, hematopoietic cells and progenitors with broader potentials are progressively generated. Mammalian hematopoietic development begins in extra-embryonic structures and continues within the embryo proper. In the conceptus, the mesoderm is patterned along the anterior-posterior (A-P) axis. The positional identity of the mesoderm on the A-P axis is regulated by Hox genes. Cdx genes, another homeobox gene family, are required for the posterior growth of axial tissues during development. Cdx genes are known to act upstream of Hox. The first evidence for a role for Cdx in
hematopoiesis was established in zebrafish. Using embryoid bodies, it was shown that the Cdx genes promote embryonic
hematopoiesis in the mouse by upregulating target Hox genes. Induction of Cdx4 promotes proliferation of hematopoietic progenitors. HSCs were more successfully derived from ESCs upon Cdx4 and Hoxb4 induction. Cdx gene deficiency jeopardizes embryonic
hematopoiesis, with severe consequences for blood development upon Cdx2 mutations. As adult Cdx4 knockout mice only displayed minimal hematopoietic abnormalities, Cdx4 is dispensable for adult
hematopoiesis. Previous studies on Cdx1 and Cdx2 mutants did not report any hematopoietic malformations either. However, it was demonstrated that overexpression of Cdx4 promotes leukemia in adult mice and that ectopic expression of Cdx2 is a key event in myeloid leukemia. The Cdx genes thus act as stimulators of hematopoietic progenitor maintenance and proliferation. Loss of function of Cdx impairs embryonic
hematopoiesis, whereas gain of function in the adult bone marrow results in overproliferation of hematopoietic progenitors, which can instigate leukemia.
Advisors/Committee Members: Deschamps, J..
Subjects/Keywords: hematopoiesis; mouse; Cdx; leukemia
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
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APA (6th Edition):
Lange, T. A. D. (2011). The role of Cdx in embryonic and adult mammalian hematopoiesis. (Masters Thesis). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/209132
Chicago Manual of Style (16th Edition):
Lange, T A D. “The role of Cdx in embryonic and adult mammalian hematopoiesis.” 2011. Masters Thesis, Universiteit Utrecht. Accessed March 04, 2021.
http://dspace.library.uu.nl:8080/handle/1874/209132.
MLA Handbook (7th Edition):
Lange, T A D. “The role of Cdx in embryonic and adult mammalian hematopoiesis.” 2011. Web. 04 Mar 2021.
Vancouver:
Lange TAD. The role of Cdx in embryonic and adult mammalian hematopoiesis. [Internet] [Masters thesis]. Universiteit Utrecht; 2011. [cited 2021 Mar 04].
Available from: http://dspace.library.uu.nl:8080/handle/1874/209132.
Council of Science Editors:
Lange TAD. The role of Cdx in embryonic and adult mammalian hematopoiesis. [Masters Thesis]. Universiteit Utrecht; 2011. Available from: http://dspace.library.uu.nl:8080/handle/1874/209132

University of Rochester
5.
Peslak, Scott Alan.
Erythropoiesis: Injury and Recovery.
Degree: PhD, 2012, University of Rochester
URL: http://hdl.handle.net/1802/21468
► Erythropoiesis is a robust process of cellular expansion and maturation that is required to maintain the massive steady-state red blood cell mass. However, anemia is…
(more)
▼ Erythropoiesis is a robust process of cellular
expansion and maturation that is
required to maintain the massive
steady-state red blood cell mass. However,
anemia is common
following clastogenic injury such as total body irradiation
(TBI),
suggesting that erythroid progenitors and precursors may be highly
sensitive targets of radiation. Here, we explore the endogenous
injury and
recovery processes of the erythron following 4 Gy TBI
of C57BL/6 mice.
Functional colony assays were used to analyze
erythroid progenitors,
including day 7 burst-forming units (d7
BFU-E) and more mature d3 BFU-E
and colony-forming units (CFU-E),
and imaging flow cytometry was utilized to
quantify erythroblast
precursors, consisting of immature proerythroblasts and
progressively more mature basophilic, polychromatophilic, and
orthochromatic erythroblasts. We find that essentially all bone
marrow and
splenic erythroid progenitors and precursors are lost
within two days following
4 Gy TBI. Phenotypic CFU-E and
proerythroblasts in the bone marrow exhibit
preferential apoptotic
loss immediately following sublethal irradiation,
revealing a
functional transition at the proerythroblast to basophilic
erythroblast maturational stages characterized by a shift from a
pro-apoptotic
to an anti-apoptotic phenotype. Following this
initial loss, erythroid recovery is
characterized by specific
expansion of late-stage erythroid progenitors (d3
BFU-E and CFU-E)
in the bone marrow that is dependent on endogenous
erythropoietin
(EPO) induction. This robust progenitor expansion is followed
by a
wave of maturing erythroid precursors in the bone marrow and their
transient emergence in the bloodstream before re-initiation of
extramedullary
erythropoiesis in the spleen. Furthermore, we find
that bone marrow
macrophages, which constitute the erythroid
precursor microenvironmental
niche, are relatively radioresistant
and form robust erythroblast islands post-4
Gy TBI during
erythroid precursor recovery. We conclude that sublethal
radiation
serves as a model of endogenous stress erythropoiesis that is
characterized by specific injury to the extravascular erythron,
initial expansion
and maturation of EPO-responsive late-stage
progenitors exclusively in the
bone marrow, and subsequent
reseeding of extramedullary sites. This model
will facilitate the
study of mechanisms regulating erythropoiesis in bone
marrow and
extramedullary sites as well as the functional evaluation of
erythroid lineage-directed therapeutics to mitigate cellular
injury.
Subjects/Keywords: Erythropoiesis; Hematopoiesis; Radiation; Erythroid Progenitor
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Peslak, S. A. (2012). Erythropoiesis: Injury and Recovery. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/21468
Chicago Manual of Style (16th Edition):
Peslak, Scott Alan. “Erythropoiesis: Injury and Recovery.” 2012. Doctoral Dissertation, University of Rochester. Accessed March 04, 2021.
http://hdl.handle.net/1802/21468.
MLA Handbook (7th Edition):
Peslak, Scott Alan. “Erythropoiesis: Injury and Recovery.” 2012. Web. 04 Mar 2021.
Vancouver:
Peslak SA. Erythropoiesis: Injury and Recovery. [Internet] [Doctoral dissertation]. University of Rochester; 2012. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1802/21468.
Council of Science Editors:
Peslak SA. Erythropoiesis: Injury and Recovery. [Doctoral Dissertation]. University of Rochester; 2012. Available from: http://hdl.handle.net/1802/21468

Loyola University Chicago
6.
Birch, Noah Warren.
Critical Functions Specified by the MLL CXXC Domain
Determine Leukemogenic Capacity.
Degree: PhD, Molecular and Cellular Biochemistry
Program, 2013, Loyola University Chicago
URL: https://ecommons.luc.edu/luc_diss/504
► TheMixed Lineage Leukemia(MLL) gene can participate in chromosomal translocations which generate a fusion protein leading to acute leukemia. A better understanding of how MLL…
(more)
▼ TheMixed Lineage Leukemia(MLL)
gene can participate in chromosomal translocations which generate a
fusion protein leading to acute leukemia. A better understanding of
how MLL fusion proteins contribute to leukemia is necessary in
order to develop more effective treatments. In my dissertation
project, I investigated the functional role of amino acids within
the MLL CXXC domain to determine how specific residues contribute
to leukemogenic capacity. MLL fusion proteins
retain the amino-terminal portion of MLL including the CXXC
DNA-binding domain while the carboxy-terminal portion is comprised
of a fusion partner. The closest homolog of MLL, MLL2
(alternatively named MLL4), also contains a similar CXXC domain,
yet an artificial MLL2 fusion protein is unable to transform
cellsin vitro. I hypothesized that specific amino acid differences
between the MLL and MLL2 CXXC domains account for differences in
leukemogenic capacity. To test this hypothesis, the MLL2 CXXC
domain was cloned into the context of the well-studied MLL-AF9
fusion protein to generate an artificial MLL/MLL2-AF9 chimera.
Amino acid substitutions were then introduced within the MLL2 CXXC
domain of this synthetic chimera to restore residues to the MLL
sequence. By comparing residues of the MLL and MLL2 CXXC domains in
colony formation and protein binding assays, critical amino acids
were identified on both the DNA-binding surface and on the
opposite, non-DNA-contact surface of the CXXC.
Cysteine 1188 of the MLL CXXC domain is the only
non-zinc-coordinating cysteine residue within the CXXC domain. This
residue is critically positioned on the DNA-binding surface with
susceptibility to post-translational modification. I hypothesized
that the Cys1188 may be physiologically altered to regulate
DNA-binding affinity. Transformed MLL-AF9 progenitor cells were
treated with modifying agents or grown under conditions of varying
oxygen concentration. The MLL-AF9 cells showed a modest
susceptibility to parthenolide treatmentin vitrobut showed no
significant differences in proliferation when grown under
conditions of varying oxygen. The results from these studies build
on the initial work conducted in our laboratory on the MLL CXXC
domain and Cys1188 providing valuable direction for future
investigations which may eventually allow for therapeutic targeting
of the CXXC domain in MLL-associated
leukemia.
Subjects/Keywords: Hematopoiesis; Leukemia; MLL; MLL2; Biochemistry
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Birch, N. W. (2013). Critical Functions Specified by the MLL CXXC Domain
Determine Leukemogenic Capacity. (Doctoral Dissertation). Loyola University Chicago. Retrieved from https://ecommons.luc.edu/luc_diss/504
Chicago Manual of Style (16th Edition):
Birch, Noah Warren. “Critical Functions Specified by the MLL CXXC Domain
Determine Leukemogenic Capacity.” 2013. Doctoral Dissertation, Loyola University Chicago. Accessed March 04, 2021.
https://ecommons.luc.edu/luc_diss/504.
MLA Handbook (7th Edition):
Birch, Noah Warren. “Critical Functions Specified by the MLL CXXC Domain
Determine Leukemogenic Capacity.” 2013. Web. 04 Mar 2021.
Vancouver:
Birch NW. Critical Functions Specified by the MLL CXXC Domain
Determine Leukemogenic Capacity. [Internet] [Doctoral dissertation]. Loyola University Chicago; 2013. [cited 2021 Mar 04].
Available from: https://ecommons.luc.edu/luc_diss/504.
Council of Science Editors:
Birch NW. Critical Functions Specified by the MLL CXXC Domain
Determine Leukemogenic Capacity. [Doctoral Dissertation]. Loyola University Chicago; 2013. Available from: https://ecommons.luc.edu/luc_diss/504

McMaster University
7.
Holzapfel, Nicholas.
Investigating the Role of the RNA-Binding Protein MUSASHI-2 (MSI2) in Normal Hematopoiesis and Leukemia.
Degree: PhD, 2016, McMaster University
URL: http://hdl.handle.net/11375/20628
► Musashi-2 (MSI2), a member of the Musashi family of RNA-binding proteins, is thought to play a critical role in the maintenance of stem cell populations…
(more)
▼ Musashi-2 (MSI2), a member of the Musashi family of RNA-binding proteins, is thought to play a critical role in the maintenance of stem cell populations and in the formation of aggressive tumours. Multiple studies indicate that MSI2 plays an important role in the maintenance of hematopoietic stem cell (HSC) populations and recent studies in humans identify MSI2 as an independent prognostic factor for overall survival in patients with Acute Myeloid Leukemia (AML). Importantly, though correlative studies implicate MSI2 as a contributor to aggressive disease in human AML, no study to date has attempted to analyze the functional role of MSI2 in primary human AML samples. Furthermore, though MSI2 is critical for the maintenance of HSCs, the mechanisms through which MSI2 functions are unknown. The work presented in this thesis elucidates the biochemical mechanisms through which MSI2 functions and examines the functional role of MSI2 in human AML.
Using a lentiviral-mediated shRNA knockdown of MSI2, I demonstrate that MSI2 is critical for the maintenance of human AML. A loss of MSI2 greatly impairs the ability of AML samples to maintain disease in a xenotransplantation assay. MSI2 is an RNA binding protein that is thought to repress the translation of target mRNAs in the cytoplasm and prevent the maturation of microRNAs (miRNAs) in the nucleus. The targets of MSI2 are believed to be potent regulators of stem-ness and dysregulation of these targets could very well contribute to neoplastic transformation. Cross-linking immunoprecipitation followed by next generation sequencing (CLIP-Seq), revealed the RNA binding properties of MSI2 and the RNA targets bound by MSI2. To identify novel MSI2 protein interactors, the MSI2 locus was endogenously tagged with the promiscuous biotin ligase BirA* and subjected to BioID analysis. When compared to appropriate controls, we were able to robustly identify proteins that associate with MSI2. The analysis of one of these protein binding partners, Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) reveals a critical role in the normal function of HSCs.
Thesis
Doctor of Philosophy (PhD)
The hematopoietic system is responsible for the production of billions of mature cells everyday. These mature cells are “differentiated”, meaning that they have gone through a process that has allowed them to become specialized to perform a very specific role. Throughout the process of differentiation, most functional cells lose their ability to proliferate. The continued production of these functional cells comes from a pool of rare, quiescent, hematopoietic stem cells (HSC). These cells maintain the production of mature cells throughout the lifetime of an organism. The Musashi-2 (MSI2) protein has been identified as a protein that is critical for the normal function of HSCs. By altering the levels of the MSI2, it is possible to greatly impair or enhance the activity of HSCs. Moreover, correlative studies implicate MSI2 as a contributor to aggressive Acute Myeloid Leukemia (AML), a…
Advisors/Committee Members: Hope, Kritstin, Biochemistry.
Subjects/Keywords: RNA-Binding Protein; Musashi; Hematopoiesis
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Holzapfel, N. (2016). Investigating the Role of the RNA-Binding Protein MUSASHI-2 (MSI2) in Normal Hematopoiesis and Leukemia. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/20628
Chicago Manual of Style (16th Edition):
Holzapfel, Nicholas. “Investigating the Role of the RNA-Binding Protein MUSASHI-2 (MSI2) in Normal Hematopoiesis and Leukemia.” 2016. Doctoral Dissertation, McMaster University. Accessed March 04, 2021.
http://hdl.handle.net/11375/20628.
MLA Handbook (7th Edition):
Holzapfel, Nicholas. “Investigating the Role of the RNA-Binding Protein MUSASHI-2 (MSI2) in Normal Hematopoiesis and Leukemia.” 2016. Web. 04 Mar 2021.
Vancouver:
Holzapfel N. Investigating the Role of the RNA-Binding Protein MUSASHI-2 (MSI2) in Normal Hematopoiesis and Leukemia. [Internet] [Doctoral dissertation]. McMaster University; 2016. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/11375/20628.
Council of Science Editors:
Holzapfel N. Investigating the Role of the RNA-Binding Protein MUSASHI-2 (MSI2) in Normal Hematopoiesis and Leukemia. [Doctoral Dissertation]. McMaster University; 2016. Available from: http://hdl.handle.net/11375/20628

University of Toronto
8.
Luca, Alice Maria.
Regulation of Hematopoietic Progenitor Formation in a Shwachman Diamond Syndrome Induced Pluripotent Stem Cell Disease Model.
Degree: 2015, University of Toronto
URL: http://hdl.handle.net/1807/70490
► Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disease, with 90% of SDS patients carrying a mutation in the SBDS gene. Due to limited…
(more)
▼ Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disease, with 90% of SDS patients carrying a mutation in the SBDS gene. Due to limited efficacy or toxicity of current treatments available, and the otherwise reduced life expectancy of SDS patients, novel therapeutic strategies are needed. Since the main morbidity and mortality are related to the blood dyscrasia, studying hematopoiesis will help characterize the hematological phenotype. We hypothesized that the definitive wave of hematopoiesis is markedly impaired. We generated SDS iPSCs that recapitulated the human SDS disease, specifically, the reduced blood cell formation. The SDS iPSCs showed a defect in definitive hematopoiesis, with a marked reduction in the hemogenic endothelium population. We did not observe a defect in primitive hematopoiesis. Our study sheds light on the onset and progression of the SDS hematopoietic phenotype, and provides a platform for the development of novel, potential therapeutic targets to improve patient care.
M.Sc.
Advisors/Committee Members: Dror, Yigal, Medical Science.
Subjects/Keywords: hematopoiesis; iPSCs; shwachman; 0758
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MLA ·
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APA (6th Edition):
Luca, A. M. (2015). Regulation of Hematopoietic Progenitor Formation in a Shwachman Diamond Syndrome Induced Pluripotent Stem Cell Disease Model. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/70490
Chicago Manual of Style (16th Edition):
Luca, Alice Maria. “Regulation of Hematopoietic Progenitor Formation in a Shwachman Diamond Syndrome Induced Pluripotent Stem Cell Disease Model.” 2015. Masters Thesis, University of Toronto. Accessed March 04, 2021.
http://hdl.handle.net/1807/70490.
MLA Handbook (7th Edition):
Luca, Alice Maria. “Regulation of Hematopoietic Progenitor Formation in a Shwachman Diamond Syndrome Induced Pluripotent Stem Cell Disease Model.” 2015. Web. 04 Mar 2021.
Vancouver:
Luca AM. Regulation of Hematopoietic Progenitor Formation in a Shwachman Diamond Syndrome Induced Pluripotent Stem Cell Disease Model. [Internet] [Masters thesis]. University of Toronto; 2015. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1807/70490.
Council of Science Editors:
Luca AM. Regulation of Hematopoietic Progenitor Formation in a Shwachman Diamond Syndrome Induced Pluripotent Stem Cell Disease Model. [Masters Thesis]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/70490

University of Ottawa
9.
Rothberg, Janet L.
Polycomb-like 2 (Mtf2/Pcl2) is Required for Epigenetic Regulation of Hematopoiesis
.
Degree: 2016, University of Ottawa
URL: http://hdl.handle.net/10393/35323
► Polycomb proteins are epigenetic regulators that are critical in mediating gene repression at critical stages during development. Core and accessory proteins make up the Polycomb…
(more)
▼ Polycomb proteins are epigenetic regulators that are critical in mediating gene repression at critical stages during development. Core and accessory proteins make up the Polycomb Repressive Complex 2 (PRC2), which is responsible for trimethylation of lysine 27 on histone 3 (H3K27me3), leading to maintenance of chromatin compaction and sustained gene repression. Classically, Polycomb accessory proteins are often thought of as having minor roles in fine-tuning the repressive action of PRC2. Their actions have often been attributed to chromatin recognition, targeting to specific loci and enhancing methyltransferase activity. In our previous work in mouse embryonic stem cells (ESCs), we showed that Polycomb-like 2 (Mtf2/Pcl2) is critical for PRC2-mediated regulation of stem cell self-renewal through feed-forward control of the pluripotency network. In moving beyond the ESC model system, we sought to interrogate the role of Mtf2 in vivo by creating a gene-targeted knockout mouse model. Surprisingly, we discovered a tissue-specific role for Mtf2 in controlling erythroid maturation and hematopoietic stem cell self-renewal. Via its regulation of other PRC2 members, Mtf2 is critical for global H3K27me3 methylation at promoter-proximal sites in developing erythroblasts. Thus, Mtf2 is required for proper maturation of erythroblasts. Loss of Mtf2 also reduces HSC self-renewal leading to stem cell pool exhaustion. Additionally, misregulation of Mtf2 in leukemia models contributes to massive leukemic blast expansion at the expense of leukemic stem cell self-renewal. In the developing hematopoietic system, Mtf2 functions as a core complex member, controlling epigenetic regulation of self-renewal and maturation of both stem and committed cells.
Subjects/Keywords: polycomb;
hematopoiesis;
erythropoiesis;
stem cells
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Rothberg, J. L. (2016). Polycomb-like 2 (Mtf2/Pcl2) is Required for Epigenetic Regulation of Hematopoiesis
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/35323
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Rothberg, Janet L. “Polycomb-like 2 (Mtf2/Pcl2) is Required for Epigenetic Regulation of Hematopoiesis
.” 2016. Thesis, University of Ottawa. Accessed March 04, 2021.
http://hdl.handle.net/10393/35323.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Rothberg, Janet L. “Polycomb-like 2 (Mtf2/Pcl2) is Required for Epigenetic Regulation of Hematopoiesis
.” 2016. Web. 04 Mar 2021.
Vancouver:
Rothberg JL. Polycomb-like 2 (Mtf2/Pcl2) is Required for Epigenetic Regulation of Hematopoiesis
. [Internet] [Thesis]. University of Ottawa; 2016. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/10393/35323.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Rothberg JL. Polycomb-like 2 (Mtf2/Pcl2) is Required for Epigenetic Regulation of Hematopoiesis
. [Thesis]. University of Ottawa; 2016. Available from: http://hdl.handle.net/10393/35323
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Washington
10.
Duggan, Jeffrey Mitchell.
BCAP functions as a dynamic regulator of hematopoiesis and myeloid cell development.
Degree: PhD, 2017, University of Washington
URL: http://hdl.handle.net/1773/38641
► Hematopoiesis governs the production of mature cells of the lymphoid, myeloid and erythroid lineages. This process occurs in the bone marrow of adult mammals, and…
(more)
▼ Hematopoiesis governs the production of mature cells of the lymphoid, myeloid and erythroid lineages. This process occurs in the bone marrow of adult mammals, and generates these lineages throughout life. Furthermore,
hematopoiesis is sensitive to multiple insults that drive demand for new hematopoietic cell differentiation, including infection, inflammation and myeloablation. These situations of demand alter hematopoietic differentiation to favor myeloid cell production, in a process known as emergency myelopoiesis. Both steady state
hematopoiesis and emergency myelopoiesis are tightly regulated by a variety of signals in order to properly control the output of the different hematopoietic lineages. BCAP (B cell adaptor for PI-3 kinase) is a signaling adaptor protein expressed in hematopoietic cells, where it has a wide array of functions. Here we show that BCAP is expressed in the Hematopoietic Stem and Progenitor cells in the bone marrow, and acts as an inhibitor of myeloid cell development in both the steady state and during demand situations. Furthermore, we show that BCAP inhibits proliferation of the Long-Term Hematopoietic Stem cells, and therefore may regulate the quiescence and/or the self-renewal of this population in the BM. Overall, we have identified BCAP as a novel dynamic regulator of
hematopoiesis and myeloid cell development.
Advisors/Committee Members: Hamerman, Jessica A (advisor).
Subjects/Keywords: BCAP; hematopoiesis; Immunology; Immunology
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Duggan, J. M. (2017). BCAP functions as a dynamic regulator of hematopoiesis and myeloid cell development. (Doctoral Dissertation). University of Washington. Retrieved from http://hdl.handle.net/1773/38641
Chicago Manual of Style (16th Edition):
Duggan, Jeffrey Mitchell. “BCAP functions as a dynamic regulator of hematopoiesis and myeloid cell development.” 2017. Doctoral Dissertation, University of Washington. Accessed March 04, 2021.
http://hdl.handle.net/1773/38641.
MLA Handbook (7th Edition):
Duggan, Jeffrey Mitchell. “BCAP functions as a dynamic regulator of hematopoiesis and myeloid cell development.” 2017. Web. 04 Mar 2021.
Vancouver:
Duggan JM. BCAP functions as a dynamic regulator of hematopoiesis and myeloid cell development. [Internet] [Doctoral dissertation]. University of Washington; 2017. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1773/38641.
Council of Science Editors:
Duggan JM. BCAP functions as a dynamic regulator of hematopoiesis and myeloid cell development. [Doctoral Dissertation]. University of Washington; 2017. Available from: http://hdl.handle.net/1773/38641
11.
Palande, Karishma.
Redox-Controlled Signaling in Normal Myeloid Cell Development and Leukemia.
Degree: 2011, Erasmus University Medical Center
URL: http://hdl.handle.net/1765/32457
► textabstractThe word hematopoiesis is derived from the greek words, haima meaning blood and poiesis meaning to make. Hematopoiesis is a tightly regulated process which ensures…
(more)
▼ textabstractThe word hematopoiesis is derived from the greek words, haima meaning blood and poiesis
meaning to make. Hematopoiesis is a tightly regulated process which ensures production of
appropriate amounts of different blood cell types. All blood cell types are derived from pluripotent
hematopoietic stem cells (HSCs). The HSCs are capable of self renewal. Committed
myeloid progenitor cells are derived from the HSCs. Committed myeloid progenitor cells are
able to proliferate and differentiate into mature blood cells like, granulocytes (neutrophils,
eosinophils, basophils), lymphocytes, erythrocytes, platelets, macrophages, natural killer
cells, dendritic cells and mast cells. During embryogenesis HSCs develop in the aorta-gonadmesonephros
(AGM) region. HSCs migrate to the fetal liver which is the main site of
hematopoiesis until birth. After birth, the bone marrow takes over as the primary site of
hematopoiesis.
Subjects/Keywords: hematopoiesis; leukemia
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Palande, K. (2011). Redox-Controlled Signaling in Normal Myeloid Cell Development and Leukemia. (Doctoral Dissertation). Erasmus University Medical Center. Retrieved from http://hdl.handle.net/1765/32457
Chicago Manual of Style (16th Edition):
Palande, Karishma. “Redox-Controlled Signaling in Normal Myeloid Cell Development and Leukemia.” 2011. Doctoral Dissertation, Erasmus University Medical Center. Accessed March 04, 2021.
http://hdl.handle.net/1765/32457.
MLA Handbook (7th Edition):
Palande, Karishma. “Redox-Controlled Signaling in Normal Myeloid Cell Development and Leukemia.” 2011. Web. 04 Mar 2021.
Vancouver:
Palande K. Redox-Controlled Signaling in Normal Myeloid Cell Development and Leukemia. [Internet] [Doctoral dissertation]. Erasmus University Medical Center; 2011. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1765/32457.
Council of Science Editors:
Palande K. Redox-Controlled Signaling in Normal Myeloid Cell Development and Leukemia. [Doctoral Dissertation]. Erasmus University Medical Center; 2011. Available from: http://hdl.handle.net/1765/32457
12.
ANG HEATHER YIN-KUAN.
DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS.
Degree: 2012, National University of Singapore
URL: http://scholarbank.nus.edu.sg/handle/10635/47634
Subjects/Keywords: Reprogramming; Hematopoiesis
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
YIN-KUAN, A. H. (2012). DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS. (Thesis). National University of Singapore. Retrieved from http://scholarbank.nus.edu.sg/handle/10635/47634
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
YIN-KUAN, ANG HEATHER. “DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS.” 2012. Thesis, National University of Singapore. Accessed March 04, 2021.
http://scholarbank.nus.edu.sg/handle/10635/47634.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
YIN-KUAN, ANG HEATHER. “DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS.” 2012. Web. 04 Mar 2021.
Vancouver:
YIN-KUAN AH. DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS. [Internet] [Thesis]. National University of Singapore; 2012. [cited 2021 Mar 04].
Available from: http://scholarbank.nus.edu.sg/handle/10635/47634.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
YIN-KUAN AH. DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS. [Thesis]. National University of Singapore; 2012. Available from: http://scholarbank.nus.edu.sg/handle/10635/47634
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
13.
XU JIN.
Study of definitive hematopoiesis in zebrafish.
Degree: 2008, National University of Singapore
URL: https://scholarbank.nus.edu.sg/handle/10635/160971
Subjects/Keywords: zebrafish hematopoiesis
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
JIN, X. (2008). Study of definitive hematopoiesis in zebrafish. (Thesis). National University of Singapore. Retrieved from https://scholarbank.nus.edu.sg/handle/10635/160971
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
JIN, XU. “Study of definitive hematopoiesis in zebrafish.” 2008. Thesis, National University of Singapore. Accessed March 04, 2021.
https://scholarbank.nus.edu.sg/handle/10635/160971.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
JIN, XU. “Study of definitive hematopoiesis in zebrafish.” 2008. Web. 04 Mar 2021.
Vancouver:
JIN X. Study of definitive hematopoiesis in zebrafish. [Internet] [Thesis]. National University of Singapore; 2008. [cited 2021 Mar 04].
Available from: https://scholarbank.nus.edu.sg/handle/10635/160971.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
JIN X. Study of definitive hematopoiesis in zebrafish. [Thesis]. National University of Singapore; 2008. Available from: https://scholarbank.nus.edu.sg/handle/10635/160971
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Notre Dame
14.
Jessica Renee Stoller-Conrad.
Determination and Characterization of Novel Genes
Influencing Drosophila Hematopoietic Development</h1>.
Degree: Biological Sciences, 2012, University of Notre Dame
URL: https://curate.nd.edu/show/k6439z92b62
► Blood development, or hematopoiesis, is an evolutionarily conserved process that is essential to life in many organisms. The hematopoetic development of Drosophila melanogaster is…
(more)
▼ Blood development, or
hematopoiesis, is an
evolutionarily conserved process that is essential to life in many
organisms. The hematopoetic development of Drosophila melanogaster
is an effective genetic and functional model of the myeloid lineage
of vertebrate
hematopoiesis, due to conserved signaling pathways
and transcription factors dictating cell proliferation and
differentiation. In both vertebrate and Drosophila
hematopoiesis,
the differentiated blood cells, or hemocytes, form from a common
hematopoietic precursor cell. Both the hematopoietic stem cells
(HSCs) in vertebrates, and the hemocyte progenitors in Drosophila,
asymmetrically divide into one pluripotent stem cell and one cell
that has been committed to a path of differentiation. Two genes
whose functions have been studied in the differentiation of
germline stem cells of Drosophila, bag-of-marbles (bam) and zero
population growth (zpg), and have been found by our lab to be
necessary for normal larval
hematopoiesis. Preliminary data I have
collected from a sensitized genetic screen suggest that a negative
regulator of translational initiation, NAT1 (N-Acetyltransferase
1), may be necessary for proper Bam function in the larval lymph
gland. In addition, phenotypic analysis of zpg homozygous null
mutants and zpg RNAi knockdown suggest that zpg is necessary for
proper differentiation of mature crystal cells and it represses
lamellocyte fate in the hematopoietic organ, the lymph gland (LG).
Though bam and zpg were originally thought to be specific to the
germline, we hypothesize that these and other factors involved in
germline stem cell maintenance and differentiation may also be
important in hematopoietic progenitor maintenance and
differentiation.
Advisors/Committee Members: Zachary Schafer, Committee Member, Rebecca Wingert, Committee Member, Robert A. Schulz, Committee Chair.
Subjects/Keywords: genetics; hematopoiesis; development; Drosophila
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Stoller-Conrad, J. R. (2012). Determination and Characterization of Novel Genes
Influencing Drosophila Hematopoietic Development</h1>. (Thesis). University of Notre Dame. Retrieved from https://curate.nd.edu/show/k6439z92b62
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Stoller-Conrad, Jessica Renee. “Determination and Characterization of Novel Genes
Influencing Drosophila Hematopoietic Development</h1>.” 2012. Thesis, University of Notre Dame. Accessed March 04, 2021.
https://curate.nd.edu/show/k6439z92b62.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Stoller-Conrad, Jessica Renee. “Determination and Characterization of Novel Genes
Influencing Drosophila Hematopoietic Development</h1>.” 2012. Web. 04 Mar 2021.
Vancouver:
Stoller-Conrad JR. Determination and Characterization of Novel Genes
Influencing Drosophila Hematopoietic Development</h1>. [Internet] [Thesis]. University of Notre Dame; 2012. [cited 2021 Mar 04].
Available from: https://curate.nd.edu/show/k6439z92b62.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Stoller-Conrad JR. Determination and Characterization of Novel Genes
Influencing Drosophila Hematopoietic Development</h1>. [Thesis]. University of Notre Dame; 2012. Available from: https://curate.nd.edu/show/k6439z92b62
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Toronto
15.
Csaszar, Elizabeth.
Feedback-mediated Regulation of Human Hematopoietic Stem Cell Fate.
Degree: 2013, University of Toronto
URL: http://hdl.handle.net/1807/70068
► Umbilical cord blood (UCB) cells fill a clinical need for hematopoietic stem and progenitor cell (HSPC) transplantation, and the ex vivo expansion of these cells…
(more)
▼ Umbilical cord blood (UCB) cells fill a clinical need for hematopoietic stem and progenitor cell (HSPC) transplantation, and the ex vivo expansion of these cells provides an approach to increase their clinical relevance. Ex vivo HSPC expansion has been limited by a poor understanding of the interplay between stem cell autonomous and feedback mediated regulators. We hypothesized that developing strategies to modulate the HSPC microenvironment would enable enhanced expansion of these cells and a greater insight into the underlying biologic mechanisms. We developed a system for the optimized delivery of the transcription factor HOXB4 to human hematopoietic culture and revealed new insights into the context-dependent potentials and limitations of HOXB4. We investigated approaches for the global reduction of inhibitory feedback signaling and developed a fed-batch system that minimizes endogenously produced factors to create a more supportive environment for HSPC self-renewal. This strategy led to an 11-fold expansion of long-term repopulating HSCs in a clinically relevant bioreactor, producing a novel system for ex vivo expansion and generating a platform to assess HSPC enhancing factors. By combining the fed-batch system with the Notch Delta-1 ligand (DL1), we identified a mechanism whereby DL1 initiated a conversion from IL-6 cis-signaling to trans-signaling, resulting in the modulation of mature cell population production. This demonstrated the impact of cell lineage skewing on microenvironment regulation and the expansion of HSPCs. This work demonstrates how cell-cell interactions and feedback mediated signaling are critical regulators of HSPCs and the manipulation of these regulators can be used both to engineer HSPC expansion processes and to identify novel mechanisms within the hematopoietic system. This provides an important step towards the development of robust methods for the ex vivo expansion of UCB-derived cells and the ultimate goal of achieving cures in hematologic disease.
PhD
Advisors/Committee Members: Zandstra, Peter, Chemical Engineering and Applied Chemistry.
Subjects/Keywords: Stem cell bioengineering; hematopoiesis; 0541
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Csaszar, E. (2013). Feedback-mediated Regulation of Human Hematopoietic Stem Cell Fate. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/70068
Chicago Manual of Style (16th Edition):
Csaszar, Elizabeth. “Feedback-mediated Regulation of Human Hematopoietic Stem Cell Fate.” 2013. Doctoral Dissertation, University of Toronto. Accessed March 04, 2021.
http://hdl.handle.net/1807/70068.
MLA Handbook (7th Edition):
Csaszar, Elizabeth. “Feedback-mediated Regulation of Human Hematopoietic Stem Cell Fate.” 2013. Web. 04 Mar 2021.
Vancouver:
Csaszar E. Feedback-mediated Regulation of Human Hematopoietic Stem Cell Fate. [Internet] [Doctoral dissertation]. University of Toronto; 2013. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1807/70068.
Council of Science Editors:
Csaszar E. Feedback-mediated Regulation of Human Hematopoietic Stem Cell Fate. [Doctoral Dissertation]. University of Toronto; 2013. Available from: http://hdl.handle.net/1807/70068

University of Melbourne
16.
Ang, Chow Hiang.
Role of Npm1 in normal hematopoiesis and acute myeloid leukemia.
Degree: 2016, University of Melbourne
URL: http://hdl.handle.net/11343/127394
► The NPM1 gene encodes a multifunctional protein that shuttles between nucleus and cytoplasm, and is involved in diverse cellular activities including both proliferation and growth…
(more)
▼ The NPM1 gene encodes a multifunctional protein that shuttles between nucleus and cytoplasm, and is involved in diverse cellular activities including both proliferation and growth suppression of cells. Genetic alterations in NPM1 are frequently involved in hematological malignancies. The NPM1c+ mutations, which are point mutations in exon 12 of the gene, resulting in aberrant localization of the NPM protein from the nucleolus to the cytoplasm, are exclusively reported in acute myeloid leukemia (AML). Previous studies showed that constitutive homozygous deletion of Npm1 in mice causes embryonic lethality due to defects in organ development and primitive hematopoiesis. This thesis employed a tamoxifen-inducible Cre-mediated conditional Npm1 knockout mouse model to investigate aspects of the normal role of Npm1 in adult hematopoiesis and of wild-type NPM in the context of leukemia.
I showed that homozygous deletion of Npm1 in adult mice resulted in altered numbers of hematopoietic stem and progenitor cells, depletion of mature lymphoid cells and erythroid cells, and predisposed the mice to development of MDS-like hematological changes. Npm1-deficient hematopoietic stem and progenitor cells failed to proliferate normally when cultured in vitro. By using transplantation assays, I further established that Npm1-deficient hematopoietic stem cells exhibited a significantly impaired functional capacity for regeneration of blood cells in ablated hosts. Gene expression analysis of Npm1-deficient stem and progenitor cells by RNA-sequencing revealed that activation of the p53 pathway is likely to contribute the perturbed hematopoiesis caused by deletion of Npm1.
This finding was extended to investigate aspects of the significance of residual wild-type Npm1 in AML pathogenesis by using the conditional Npm1 mouse model in combination with retroviral NPM1c+ or mice harboring a constitutive Flt3-ITD mutation. I showed that unlike wild-type NPM1, expression of NPM1c+ could not revert nor influence molecular changes caused by homozygous deletion of endogenous Npm1 in hematopoietic progenitor cells, and that unlike heterozygosity of wild-type and mutant Npm1 alleles, homozygous loss of Npm1 did not promote rapid leukemogenesis when combined with the AML-associated Flt3-ITD mutation. These observations support a model in which retention of wild-type NPM activity is required in leukemia.
Subjects/Keywords: Npm1; hematopoiesis; acute myeloid leukemia
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ang, C. H. (2016). Role of Npm1 in normal hematopoiesis and acute myeloid leukemia. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/127394
Chicago Manual of Style (16th Edition):
Ang, Chow Hiang. “Role of Npm1 in normal hematopoiesis and acute myeloid leukemia.” 2016. Doctoral Dissertation, University of Melbourne. Accessed March 04, 2021.
http://hdl.handle.net/11343/127394.
MLA Handbook (7th Edition):
Ang, Chow Hiang. “Role of Npm1 in normal hematopoiesis and acute myeloid leukemia.” 2016. Web. 04 Mar 2021.
Vancouver:
Ang CH. Role of Npm1 in normal hematopoiesis and acute myeloid leukemia. [Internet] [Doctoral dissertation]. University of Melbourne; 2016. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/11343/127394.
Council of Science Editors:
Ang CH. Role of Npm1 in normal hematopoiesis and acute myeloid leukemia. [Doctoral Dissertation]. University of Melbourne; 2016. Available from: http://hdl.handle.net/11343/127394

University of Southern California
17.
Wey, Shiuan.
The role of endoplasmic reticulum protein GRP78 in normal
hematopoeises and PTEN-null leukemogenesis.
Degree: PhD, Genetic, Molecular and Cellular Biology, 2013, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/629905/rec/7218
► The endoplasmic reticulum (ER) is an intracellular organelle for protein folding, lipid synthesis and Ca²⁺ storage. It is also responsible for the transportation for most…
(more)
▼ The endoplasmic reticulum (ER) is an intracellular
organelle for protein folding, lipid synthesis and Ca²⁺ storage. It
is also responsible for the transportation for most of the
secretory and transmembrane proteins. When the protein load exceeds
the ER folding capacity, the ER undergoes stress and activates a
set of signaling cascades that is termed the unfolded protein
response (UPR). The multifunctional GRP78 is the major ER molecular
chaperone with protein folding abilities and the master regulator
of the UPR, and recently has been shown that a subfraction of it is
localized on the cell surface acting as a co-receptor for various
signaling pathway activation. ❧ Traditionally GRP78 is regarded as
protective against hypoxia and nutrient starvation prevalent in the
microenvironment of solid tumors, thus, its role in the development
of hematologic malignancies remains to be determined. In this
thesis, elevated GRP78 expression was detected in leukemic blasts
of adult patients, leukemia cell lines and inversely correlates
with time to relapse in childhood acute lymphocytic leukemia. To
directly elucidate the requirement of GRP78 in leukemogenesis, we
created a biallelic conditional knockout mouse model of GRP78 and
PTEN in the hematopoietic system. Strikingly, heterozygous
knockdown of GRP78 in PTEN null mice is sufficient to restore the
hematopoietic stem cell (HSC) population back to the normal
percentage and suppress leukemic blast cell expansion. AKT/mTOR
activation in PTEN null bone marrow cells is potently inhibited by
Grp78 heterozygosity, corresponding with suppression of the
PI3K/AKT pathway by GRP78 knockdown in leukemia cell lines. This is
the first demonstration that GRP78 is a critical effector of
leukemia progression, at least in part through control of oncogenic
AKT signaling. Furthermore, overexpression of GRP78 renders human
leukemic cells more resistant to AraC-induced apoptosis whereas
knockdown of GRP78 sensitizes them, suggesting GRP78 is a novel
potent therapeutic target for leukemia. ❧ Hematopoietic stem cell
(HSC) homeostasis in the adult bone marrow (BM) is regulated by
both intrinsic gene expression and interactions with extrinsic
factors in the microenvironment. GRP78 has been shown to be
critical for the maintenance of cellular homeostasis and prevention
of apoptosis. Homozygous knockout mice of GRP78 are embryonic
lethal at E3.5, indicating GRP78 is essential for embryonic cell
growth and pluripotent cell survival. However, this has not been
investigated in adult hematopoietic stem cells. Here we generated a
conditional knockout mouse model that acutely deletes GRP78 in the
hematopoietic system. GRP78 deficiency results in a significant
reduction of HSCs, progenitor and lymphoid cell populations yet an
increase in myeloid lineage granulocytes and monocytes in cKO mice.
The GRP78-null induced reduction of the HSC pool can be attributed
to enhanced apoptosis. In agreement, GRP78 deficient BM cells
exhibited activated UPR signaling in all three branches and induced
expression of pro-apoptotic…
Advisors/Committee Members: Lee, Amy S. (Committee Chair), Kahn, Michael (Committee Member), Shibata, Darryl K. (Committee Member).
Subjects/Keywords: GRP78; AKT; PTEN; leukemia; hematopoiesis
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Wey, S. (2013). The role of endoplasmic reticulum protein GRP78 in normal
hematopoeises and PTEN-null leukemogenesis. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/629905/rec/7218
Chicago Manual of Style (16th Edition):
Wey, Shiuan. “The role of endoplasmic reticulum protein GRP78 in normal
hematopoeises and PTEN-null leukemogenesis.” 2013. Doctoral Dissertation, University of Southern California. Accessed March 04, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/629905/rec/7218.
MLA Handbook (7th Edition):
Wey, Shiuan. “The role of endoplasmic reticulum protein GRP78 in normal
hematopoeises and PTEN-null leukemogenesis.” 2013. Web. 04 Mar 2021.
Vancouver:
Wey S. The role of endoplasmic reticulum protein GRP78 in normal
hematopoeises and PTEN-null leukemogenesis. [Internet] [Doctoral dissertation]. University of Southern California; 2013. [cited 2021 Mar 04].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/629905/rec/7218.
Council of Science Editors:
Wey S. The role of endoplasmic reticulum protein GRP78 in normal
hematopoeises and PTEN-null leukemogenesis. [Doctoral Dissertation]. University of Southern California; 2013. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/629905/rec/7218

University of Hong Kong
18.
Man, Ki-fong.
The role of calreticulin
(CALR) in vertebrate hematopoiesis.
Degree: 2016, University of Hong Kong
URL: http://hdl.handle.net/10722/237867
► Calreticulin (CALR) is a multi-functional protein mainly controlling protein folding and calcium homeostasis in endoplasmic reticulum (ER). Recently, recurrent mutations in CALR have been found…
(more)
▼ Calreticulin (CALR) is a multi-functional
protein mainly controlling protein folding and calcium homeostasis
in endoplasmic reticulum (ER). Recently, recurrent mutations in
CALR have been found in essential thrombocythemia (ET) and primary
myelofibrosis (PMF) patients without Janus kinase 2 (JAK2) or
thrombopoietin receptor (MPL) mutations. Previous studies have
shown that mutant forms of CALR interacted with MPL to activate
JAK2-STAT5 signaling pathway in myeloproliferative neoplasm (MPN).
However, the functional role of CALR in normal hematopoiesis
remains unknown. In this study, we made use of zebrafish model to
examine the unknown roles of Calr in vertebrate hematopoiesis.
A
somatic calr loss-of-function zebrafish model was generated by
co-injecting two TALEN pairs separately targeting calr exon 1 and
exon 5. Western-blot confirmed the reduction of calr protein in
whole embryos as well as adult kidney marrow cells. Somatic calr
mutations significantly increased the expression of genes
associated with myeloid lineages, including pu.1, l-plastin, mpo
and mpeg1, while decreased the expression of c-myb (hematopoietic
stem cells (HSCs)) and rag1 (lymphocytes) in definitive
hematopoiesis as shown by whole mount in situ hybridization (WISH).
The myeloid-proliferation phenotype also persisted in adult
hematopoiesis as shown by the expansion of myeloid cells in whole
kidney marrows (WKMs) examined by flow cytometry. Unlike CALR
mutations in MPN, calr loss-of-function did not affect subcellular
phospho-stat5 status in the expanded myeloid population, suggests
that calr regulates normal definitive hematopoiesis through an
alternative pathway. We initially knock-down calr with morpholino
(MO), which resulted in decrease in differentiated primitive
myeloid cells and increase in definitive HSCs as shown by WISH, and
is opposite to the results observed in calr loss-of-function model
by double TALEN injection. However, western blot showed that calr
protein level increased unexpectedly in calr morphant which might
explain the phenotypic discrepancy between calr morphants and
somatic mutants.
To model CALR mutations, TALEN was also used to
introduce frame-shifting mutations in zebrafish calr exon 9. In
particular, a 7-bp deletion mutant, which resulted in a basic
C-terminal resembling human CALR type-I and II mutations was
generated. Although low fertility and survival rate limited the
number of 7-bp mutants available for analysis, two out of four
heterozygous F2 7-bp mutants developed tumor-like tissue in the
head with infiltration of blastlike hematopoietic cells during
early adulthood. Also, the percentage of myeloid cells increased
significantly in their kidney marrows. These leukemic and MPN-like
phenotypes were not observed in wild-type siblings or 5-bp mutants
(resulted in a truncated C-terminal), under-scored the pathological
potential of the novel basic C-terminal.
In summary, we
demonstrated the previously unknown role of Calr in regulating
vertebrate definitive hematopoiesis, in particular, myelopoiesis.…
Subjects/Keywords: Hematopoiesis;
Calreticulin
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Man, K. (2016). The role of calreticulin
(CALR) in vertebrate hematopoiesis. (Thesis). University of Hong Kong. Retrieved from http://hdl.handle.net/10722/237867
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Man, Ki-fong. “The role of calreticulin
(CALR) in vertebrate hematopoiesis.” 2016. Thesis, University of Hong Kong. Accessed March 04, 2021.
http://hdl.handle.net/10722/237867.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Man, Ki-fong. “The role of calreticulin
(CALR) in vertebrate hematopoiesis.” 2016. Web. 04 Mar 2021.
Vancouver:
Man K. The role of calreticulin
(CALR) in vertebrate hematopoiesis. [Internet] [Thesis]. University of Hong Kong; 2016. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/10722/237867.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Man K. The role of calreticulin
(CALR) in vertebrate hematopoiesis. [Thesis]. University of Hong Kong; 2016. Available from: http://hdl.handle.net/10722/237867
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of British Columbia
19.
Hogge, Donna Eileen.
Genetic investigations of human hemopoiesis : studies of clonality and gene transfer to hemopoietic progenitors.
Degree: PhD, Pathology, 1987, University of British Columbia
URL: http://hdl.handle.net/2429/27316
► In most neoplasms malignant change occurs in a single cell which then proliferates. My purpose was to explore methods to study the cell that gives…
(more)
▼ In most neoplasms malignant change occurs in a single cell which then proliferates. My purpose was to explore methods to study the cell that gives rise to hemopoietic cancer and to investigate the abnormalities at a molecular level.
Cytogenetic analysis of cells from individual hemopoietic colonies revealed that monosomy 7 syndrome, a hematologic disorder of childhood, arises in a primitive cell capable of differentiating down both myeloid and erythroid pathways.
Long-term bone marrow cultures (LTC) from patients with chronic myelogenous leukemia (CML) favor the growth of Philadelphia chromosome (Ph) negative progenitors which, although cytogenetically normal, could have been part of the malignant clone at a stage prior to the development of the Ph. LTC's were initiated with cells from 2 women with CML who were heterozygous for 2 electrophoretically distinct glucose-6-phosphate dehydrogenase (G6PD) enzyme variants. In one patient, 2/11 progenitors were Ph-negative after 4 to 6 weeks in LTC and 4/30 were nonclonal by G6PD enzyme analysis, i.e. the colonies expressed the enzyme not found in the malignant clone. In this case, karyotypically normal cells were truly normal.
Next, gene transfer to human hemopoietic cells was demonstrated using recombinant retrovirus carrying the selectable marker gene, neor. With the K562 human leukemic cell line as targets up to 60% of infected cells became G418 resistant (G418r). Cloned populations of G418r cells showed unique patterns of retroviral integration in K562 DNA. When the target cells were progenitors from normal marrow, CML blood or fetal liver, the highest frequencies of G418r granulocyte-macrophage or large erythroid colonies was 16% and 5% respectively. Experiments infecting bone marrow cells in LTC with neor virus produced up to 2% G418r colonies after as long as 3 weeks in culture. Using v-src virus to infect LTC failed to perturb hemopoiesis, although infection of bone marrow-derived cells in these cultures was documented.
In summary:
1. Unique populations of hemopoietic progenitors can be identified in culture using several genetic markers including chromosomes, G6PD analysis or gene transfer. 2. The feasibility of retroviral-mediated gene transfer for use on human hemopoietic cells has been demonstrated.
Subjects/Keywords: Transfection; Hematopoiesis
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hogge, D. E. (1987). Genetic investigations of human hemopoiesis : studies of clonality and gene transfer to hemopoietic progenitors. (Doctoral Dissertation). University of British Columbia. Retrieved from http://hdl.handle.net/2429/27316
Chicago Manual of Style (16th Edition):
Hogge, Donna Eileen. “Genetic investigations of human hemopoiesis : studies of clonality and gene transfer to hemopoietic progenitors.” 1987. Doctoral Dissertation, University of British Columbia. Accessed March 04, 2021.
http://hdl.handle.net/2429/27316.
MLA Handbook (7th Edition):
Hogge, Donna Eileen. “Genetic investigations of human hemopoiesis : studies of clonality and gene transfer to hemopoietic progenitors.” 1987. Web. 04 Mar 2021.
Vancouver:
Hogge DE. Genetic investigations of human hemopoiesis : studies of clonality and gene transfer to hemopoietic progenitors. [Internet] [Doctoral dissertation]. University of British Columbia; 1987. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/2429/27316.
Council of Science Editors:
Hogge DE. Genetic investigations of human hemopoiesis : studies of clonality and gene transfer to hemopoietic progenitors. [Doctoral Dissertation]. University of British Columbia; 1987. Available from: http://hdl.handle.net/2429/27316

University of Rochester
20.
Frame, Jenna M.
Emergence and Regulation of Hemogenic Endothelium in the
Mammalian Yolk Sac.
Degree: PhD, 2015, University of Rochester
URL: http://hdl.handle.net/1802/30111
► Hematopoietic stem cells are specified during embryogenesis from a specialized population of endothelium, termed hemogenic endothelium, which resides in major embryonic arteries and requires the…
(more)
▼ Hematopoietic stem cells are specified during
embryogenesis from a specialized
population of endothelium, termed
hemogenic endothelium, which resides in major
embryonic arteries
and requires the hematopoietic transcription factor Runx1. Despite
the established presence of these functional hematopoietic stem
cells in the
midgestation mouse embryo, embryonic survival is
dependent on the earlier emergence
and differentiation of a
transient wave of yolk sac-derived erythro-myeloid progenitors.
Previously, our laboratory confirmed that erythro-myeloid
progenitors preferentially
emerge from murine embryonic stem cell
cultures. Conversely, transplantable
hematopoietic stem cells have
not yet been derived from embryonic stem cells,
indicating the
need to better understand the regulation of hematopoietic potential
during
development.
Here, we define the cellular origin of
erythro-myeloid progenitors, and begin to
address mechanisms
regulating their specification of during embryogenesis. We
confirmed reports that erythro-myeloid progenitors require Runx1
for formation, and
immunohistochemical studies strongly suggest
they are derived from hemogenic
endothelium. Subsequently, we
examined hematopoietic emergence in Runx1+/- yolk
sacs, which had
reported alterations in hematopoietic potential, and found that
reduced
Runx1 dosage both delays the emergence of erythro-myeloid
potential from hemogenic
endothelium and results in increased
proliferative potential.
In the aorta, the specification of
hematopoietic stem cell-producing hemogenic
endothelium is
dependent on embryonic circulation and β-catenin signaling.
Interestingly, in the yolk sac, we found that hemogenic endothelium
does not appear to
be restricted to arterial vasculature, and
analysis of circulation-deficient yolk sacs
revealed normal
cluster morphology and location, indicating the
endothelial-tohematopoietic
transition can occur in vivo without
blood flow. Conversely, however,
exogenous activation of β-catenin
signaling in whole yolk sacs increased hematopoietic
colony-forming activity. Subsequent in vitro assays and analysis of
β-catenin reporter
yolk sacs implicate a role for β-catenin
signaling in hemogenic endothelium. Therefore,
while emergence of
erythro-myeloid progenitors from hemogenic endothelium is not
dependent on blood flow or arterial identity, β-catenin appears to
play a common role in
hematopoietic specification from
endothelium.
Together, these data indicate the presence of
heterogeneous populations of
hemogenic endothelia in the mammalian
conceptus, and highlight the need to
understand developmental cues
that influence the hematopoietic potential of each
population in
order to efficiently derive them in vitro.
Subjects/Keywords: Hematopoiesis; Fetal Hematopoiesis; Runx1; Embryogenesis; Erythro-Myeloid Progenitors
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Frame, J. M. (2015). Emergence and Regulation of Hemogenic Endothelium in the
Mammalian Yolk Sac. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/30111
Chicago Manual of Style (16th Edition):
Frame, Jenna M. “Emergence and Regulation of Hemogenic Endothelium in the
Mammalian Yolk Sac.” 2015. Doctoral Dissertation, University of Rochester. Accessed March 04, 2021.
http://hdl.handle.net/1802/30111.
MLA Handbook (7th Edition):
Frame, Jenna M. “Emergence and Regulation of Hemogenic Endothelium in the
Mammalian Yolk Sac.” 2015. Web. 04 Mar 2021.
Vancouver:
Frame JM. Emergence and Regulation of Hemogenic Endothelium in the
Mammalian Yolk Sac. [Internet] [Doctoral dissertation]. University of Rochester; 2015. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1802/30111.
Council of Science Editors:
Frame JM. Emergence and Regulation of Hemogenic Endothelium in the
Mammalian Yolk Sac. [Doctoral Dissertation]. University of Rochester; 2015. Available from: http://hdl.handle.net/1802/30111

University of Oxford
21.
Buchrieser, Julian.
Understanding human mononuclear phagocyte ontogeny using human induced pluripotent stem cells (iPSCs).
Degree: PhD, 2016, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:aaf18203-5f30-4d6a-8f51-3096b29af252
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730166
► Tissue-resident macrophages (MΦ) such as microglia, Kupffer and Langerhans cells derive from Myb-independent yolk sac (YS) progenitors generated before the emergence of hematopoietic stem cells…
(more)
▼ Tissue-resident macrophages (MΦ) such as microglia, Kupffer and Langerhans cells derive from Myb-independent yolk sac (YS) progenitors generated before the emergence of hematopoietic stem cells (HSCs). Myb-independent YS-derived resident MΦ self-renew locally, independently of circulating adult monocytes and HSCs. In contrast, adult blood monocytes as well as infiltrating, gut and dermal MΦ derive from Myb-dependent HSCs and are less proliferative. These findings are derived from the mouse, using gene knock-outs and lineage tracing, but their applicability to human development has not been formally demonstrated. Here I use a human pluripotent stem cell (hPSC) differentiation model of hematopoiesis, capable of monocyte/MΦ production over prolonged periods of time, as a tool to investigate human mononuclear phagocyte ontogeny. Using a transcriptomic approach I showed that hiPSC-derived monocytes/MΦ (iPS-Mo/MΦ) produced early in differentiation (first weeks) are more proliferative and less immunologically mature than iPS-Mo/MΦ produced at a later time point. I therefore hypothesised either that iPS-Mo/MΦ only become fully mature after several weeks of differentiation or that there are two developmentally distinct waves of MΦ produced over time. By comparing the transcription profile of iPS-Mo/MΦs to that of primary adult blood monocytes and fetal microglia I then showed that early and late iPS-Mo/MΦs were transcriptionally closer to fetal microglia than to adult blood monocytes. To further investigate if iPS-Mo/MΦs are indeed of the same developmental origin as MYB-independent MΦ such as microglia, I used a CRISPR-Cas9 knock-out strategy to show for the first time, that human iPS-Mo/MΦs develop in a MYB-independent, RUNX1 and SPI1 (PU.1)-dependent fashion. This result makes human iPS-Mo/MΦs developmentally related to, and a good model for, MYB-independent tissue-resident \Macros such as alveolar and kidney MΦs, microglia, Kupffer and Langerhans cells. Interestingly, while MYB was not required for the generation of iPS-Mo/MΦs, its knock-out resulted in an increase in iPS-Mo/MΦ production. To investigate this increase I developed two methods for quantifying the differentiation bottleneck occurring during hiPSC differentiation to iPS-Mo/MΦs. Those techniques highlighted a potential increase in progenitor cell generation in MYB KO cells and thus lay foundation to improve our technical understanding of EB differentiation and will enable enhanced manipulation of the EB model.
Subjects/Keywords: 612.4; Hematopoiesis; Primitive hematopoiesis; Macrophage; MYB; SPI1; RUNX1
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Buchrieser, J. (2016). Understanding human mononuclear phagocyte ontogeny using human induced pluripotent stem cells (iPSCs). (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:aaf18203-5f30-4d6a-8f51-3096b29af252 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730166
Chicago Manual of Style (16th Edition):
Buchrieser, Julian. “Understanding human mononuclear phagocyte ontogeny using human induced pluripotent stem cells (iPSCs).” 2016. Doctoral Dissertation, University of Oxford. Accessed March 04, 2021.
http://ora.ox.ac.uk/objects/uuid:aaf18203-5f30-4d6a-8f51-3096b29af252 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730166.
MLA Handbook (7th Edition):
Buchrieser, Julian. “Understanding human mononuclear phagocyte ontogeny using human induced pluripotent stem cells (iPSCs).” 2016. Web. 04 Mar 2021.
Vancouver:
Buchrieser J. Understanding human mononuclear phagocyte ontogeny using human induced pluripotent stem cells (iPSCs). [Internet] [Doctoral dissertation]. University of Oxford; 2016. [cited 2021 Mar 04].
Available from: http://ora.ox.ac.uk/objects/uuid:aaf18203-5f30-4d6a-8f51-3096b29af252 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730166.
Council of Science Editors:
Buchrieser J. Understanding human mononuclear phagocyte ontogeny using human induced pluripotent stem cells (iPSCs). [Doctoral Dissertation]. University of Oxford; 2016. Available from: http://ora.ox.ac.uk/objects/uuid:aaf18203-5f30-4d6a-8f51-3096b29af252 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730166

University of Alberta
22.
Pillay, Laura M.
Functional Characterization of Homeodomain Transcription
Factors and Retinoic Acid Signaling in Hematopoiesis.
Degree: PhD, Department of Biological Sciences, 2015, University of Alberta
URL: https://era.library.ualberta.ca/files/dz010s67m
► Improper regulation of hematopoiesis generates a spectrum of defects that range from anemia and embryonic lethality to leukemia. Identifying the molecular pathways that regulate hematopoiesis…
(more)
▼ Improper regulation of hematopoiesis generates a
spectrum of defects that range from anemia and embryonic lethality
to leukemia. Identifying the molecular pathways that regulate
hematopoiesis is therefore a major goal of both basic and clinical
biology. Vertebrate hematopoiesis occurs in two embryonic waves.
The first wave, primitive hematopoiesis, influences the morphology
of the developing embryonic circulatory system and produces
circulating erythrocytes that facilitate tissue oxygenation during
periods of rapid embryonic growth. The second, definitive wave of
hematopoiesis produces multipotent hematopoietic stem cells (HSCs)
that are able to differentiate into all mature blood cell lineages,
self-renew, and maintain adult hematopoiesis for life. A major
challenge in developmental hematopoiesis is to determine the
molecular cues that regulate each phase of hematopoiesis. Previous
analyses using vertebrate models have identified molecular pathways
that govern both primitive and definitive hematopoiesis. These
pathways are conserved among vertebrates, and the critical
mammalian hematopoietic genes have clear orthologues in zebrafish.
Using zebrafish as a model organism, we have identified essential
regulators of both primitive and definitive hematopoiesis. We have
defined a critical role for the homeodomain transcription factors
Meis1 and Pbx in regulating primitive erythropoiesis. Inhibiting
zebrafish Meis1 and Pbx protein synthesis cripples the production
of circulating erythrocytes, and generates defects in
erythropoietic gene expression. Our data place Meis1 and Pbx
upstream of gata1 in the erythropoietic transcription factor
hierarchy. We have also elucidated a novel role for retinoic acid
(RA) signaling in definitive hematopoiesis, as RA-depleted embryos
fail to produce HSCs. Previous studies have implicated RA as a
critical regulator of murine Notch1 signaling, and suggest that
endothelial cells require RA in order to adopt a hemogenic fate.
However, our research suggests that RA is required for HSC
formation prior to the formation of dorsal aorta hemogenic
endothelium and that, unlike in mice, zebrafish RA does not
regulate HSC formation through the Notch1-signaling pathway.
Previous research by our lab has implicated the homeodomain
transcription factor Hmx4 as a critical regulator of zebrafish
forebrain and ocular development, and has shown that Hmx4 modulates
RA signaling. However, prior to this work, the contribution of Hmx4
to embryonic hematopoiesis was unknown. We have identified putative
RA-independent and dependent roles for Hmx4 in regulating primitive
and definitive hematopoiesis, respectively.
Subjects/Keywords: Primitive Hematopoiesis; Hmx4; Homeodomain Transcription Factors; Hematopoiesis; Sharkey; Definitive Hematopoiesis; Meis1; Zinc Finger Nuclease; Retinoic Acid; Zebrafish; Pbx; TALEN
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Pillay, L. M. (2015). Functional Characterization of Homeodomain Transcription
Factors and Retinoic Acid Signaling in Hematopoiesis. (Doctoral Dissertation). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/dz010s67m
Chicago Manual of Style (16th Edition):
Pillay, Laura M. “Functional Characterization of Homeodomain Transcription
Factors and Retinoic Acid Signaling in Hematopoiesis.” 2015. Doctoral Dissertation, University of Alberta. Accessed March 04, 2021.
https://era.library.ualberta.ca/files/dz010s67m.
MLA Handbook (7th Edition):
Pillay, Laura M. “Functional Characterization of Homeodomain Transcription
Factors and Retinoic Acid Signaling in Hematopoiesis.” 2015. Web. 04 Mar 2021.
Vancouver:
Pillay LM. Functional Characterization of Homeodomain Transcription
Factors and Retinoic Acid Signaling in Hematopoiesis. [Internet] [Doctoral dissertation]. University of Alberta; 2015. [cited 2021 Mar 04].
Available from: https://era.library.ualberta.ca/files/dz010s67m.
Council of Science Editors:
Pillay LM. Functional Characterization of Homeodomain Transcription
Factors and Retinoic Acid Signaling in Hematopoiesis. [Doctoral Dissertation]. University of Alberta; 2015. Available from: https://era.library.ualberta.ca/files/dz010s67m

Harvard University
23.
Netravali, Ilka Arun.
Elucidation of plasmacytoid dendritic cell development.
Degree: PhD, Biology: Medical Sciences, Division of, 2014, Harvard University
URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274587
► Most currently defined hematopoietic progenitor pools are heterogeneous, contributing to uncertainty regarding the development of certain blood cells. The origins of plasmacytoid dendritic cells, for…
(more)
▼ Most currently defined hematopoietic progenitor pools are heterogeneous, contributing to uncertainty regarding the development of certain blood cells. The origins of plasmacytoid dendritic cells, for instance, have long been controversial and progenitors exclusively committed to this lineage have never been described. We show here that the fate of hematopoietic progenitors is determined in part by their surface levels of 9-O-acetyl sialic acid. Pro-plasmacytoid dendritic cells were identified as lineage negative 9-O-acetyl sialic acid low progenitors that lack myeloid and lymphoid potential but differentiate into pre-plasmacytoid dendritic cells. The latter cells are also lineage negative, 9-O-acetyl sialic acid low cells but are exclusively committed to the plasmacytoid dendritic cell lineage. Levels of 9-O-acetyl sialic acid provide a distinct way to define progenitors and thus facilitate the study of hematopoietic differentiation.
Advisors/Committee Members: Pillai, Shiv Subramaniam (advisor), Turley, Shannon (committee member), Sharpe, Arlene (committee member), Lichtman, Andrew (committee member), Clark, Rachael (committee member).
Subjects/Keywords: Immunology; hematopoiesis; plasmacytoid dendritic cell; sialic acid
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Netravali, I. A. (2014). Elucidation of plasmacytoid dendritic cell development. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274587
Chicago Manual of Style (16th Edition):
Netravali, Ilka Arun. “Elucidation of plasmacytoid dendritic cell development.” 2014. Doctoral Dissertation, Harvard University. Accessed March 04, 2021.
http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274587.
MLA Handbook (7th Edition):
Netravali, Ilka Arun. “Elucidation of plasmacytoid dendritic cell development.” 2014. Web. 04 Mar 2021.
Vancouver:
Netravali IA. Elucidation of plasmacytoid dendritic cell development. [Internet] [Doctoral dissertation]. Harvard University; 2014. [cited 2021 Mar 04].
Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274587.
Council of Science Editors:
Netravali IA. Elucidation of plasmacytoid dendritic cell development. [Doctoral Dissertation]. Harvard University; 2014. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274587

Northeastern University
24.
Peters, Michael J.
Modeling the evolutionary loss of erythroid genes by Antarctic icefishes: analysis of the hemogen gene using transgenic and mutant zebrafish.
Degree: PhD, Department of Marine and Environmental Sciences, 2018, Northeastern University
URL: http://hdl.handle.net/2047/D20293303
► The Antarctic icefishes (Channichthyidae) are the only vertebrate taxon whose species do not produce red blood cells, thereby providing a natural mutant model to study…
(more)
▼ The Antarctic icefishes (Channichthyidae) are the only vertebrate taxon whose species do not produce red blood cells, thereby providing a natural mutant model to study the regulators of blood development and disease. To identify novel regulators of erythropoiesis, I compared RNA-Seq transcriptomes from red- and white-blooded notothenioids. I find that both icefishes and their sister taxon, the dragonfishes (Bathydraconidae), model beta-spectrin mutated spherocytic anemia. Icefishes appear to have evolved morph-biased changes in expression of hematopoietic regulatory genes, including down-regulation of the histone acetyltransferase p300 and overexpression of histone deacetylase 1b. In icefishes, I characterize a frameshift mutation that truncates the P300-binding domain of Hemogen, an important erythroid transcription factor. Tol2 and CRISPR/Cas9-generated transgenic zebrafish lines reveal that hemogen is expressed in hematopoietic, renal, neural, and reproductive tissues. I find that two conserved non-coding elements differentially contribute to hemogen expression in primitive and definitive waves of hematopoiesis. CRISPR-generated mutant zebrafish lines, which replicate the C-terminal mutation in icefish hemogen, show severe anemia and growth defects. Furthermore, I show that the function of zebrafish Hemogen is dependent on acidic residues within the TAD. Thus, Antarctic icefishes evolved an intricate system for repression of erythropoiesis that is caused in part by the loss of Hemogen function.
Subjects/Keywords: anemia; CRISPR; erythropoiesis; gene editing; hematopoiesis; zebrafish
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
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APA (6th Edition):
Peters, M. J. (2018). Modeling the evolutionary loss of erythroid genes by Antarctic icefishes: analysis of the hemogen gene using transgenic and mutant zebrafish. (Doctoral Dissertation). Northeastern University. Retrieved from http://hdl.handle.net/2047/D20293303
Chicago Manual of Style (16th Edition):
Peters, Michael J. “Modeling the evolutionary loss of erythroid genes by Antarctic icefishes: analysis of the hemogen gene using transgenic and mutant zebrafish.” 2018. Doctoral Dissertation, Northeastern University. Accessed March 04, 2021.
http://hdl.handle.net/2047/D20293303.
MLA Handbook (7th Edition):
Peters, Michael J. “Modeling the evolutionary loss of erythroid genes by Antarctic icefishes: analysis of the hemogen gene using transgenic and mutant zebrafish.” 2018. Web. 04 Mar 2021.
Vancouver:
Peters MJ. Modeling the evolutionary loss of erythroid genes by Antarctic icefishes: analysis of the hemogen gene using transgenic and mutant zebrafish. [Internet] [Doctoral dissertation]. Northeastern University; 2018. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/2047/D20293303.
Council of Science Editors:
Peters MJ. Modeling the evolutionary loss of erythroid genes by Antarctic icefishes: analysis of the hemogen gene using transgenic and mutant zebrafish. [Doctoral Dissertation]. Northeastern University; 2018. Available from: http://hdl.handle.net/2047/D20293303

Boston University
25.
Dharampuriya, Priyanka.
Role of epigenetics in hematopoietic stem cell development.
Degree: MS, Medical Sciences, 2017, Boston University
URL: http://hdl.handle.net/2144/23717
► In 2106, there were 171,550 new cases of blood cancers and over one million people in the United States living with one of these disorders.…
(more)
▼ In 2106, there were 171,550 new cases of blood cancers and over one million people in the United States living with one of these disorders. Bone marrow transplants have good outcomes, but these procedures require a donor who is a perfect match, and thus many patients are unable to receive treatment. It is important to find patient-derived treatments, such as molecules which stimulate hematopoietic stem cell (HSC) formation without the need for a donor. Therefore, a study was initiated to use human-induced pluripotent stem cell (hiPSC) technology to make a patient-derived, personalized HSC.
Epigenetic regulators are divided into readers, writers, and erasers, and each of these classes has shown some effect on HSC formation. Writers add functional groups to deoxyribonucleic acid (DNA) and histone proteins, whereas erasers remove them. Readers are groups on transcription factors which interpret these changes and increase or decrease the recruitment of transcriptional machinery accordingly. In this study, a screen of 12 different candidate molecules with distinct epigenetic targets in casper zebrafish was conducted at 36 hours postfertilization (hpf) to reveal increases or decreases in definitive HSC development. The two writer molecules, C646 (histone acetyltransferase, or HAT, inhibitor) and OICR9249 (WDR5 inhibitor), and the two eraser molecules, Ex-527 (Sirt1 inhibitor) and JIB-04 (bromodomain inhibitor), showed varying degrees of increasing HSC formation. Of these molecules, C646 created the most significant increase and was further tested in the zebrafish at 48 and 72 hpf and in a murine model using ex vivo technique and a colony-forming unit (CFU) assay. In contrast to these results, the two eraser molecules, entinostat (class I histone deacetylase, or HDAC, inhibitor) and vorinostat (general HDAC inhibitor), were found to decrease HSC formation in zebrafish. The overall findings of this study provide insight into specific epigenetic regulators in HSC development and identify particular epigenetic markers that could regulate HSC formation from endothelial cells. This discovery will be a stepping stone in utilizing patient-derived hemogenic endothelial cells as a novel source of bone marrow-independent HSCs to treat patients with leukemia, lymphoma, and bone marrow cancers.
Subjects/Keywords: Medicine; HDAC; Epigenetics; Hematopoiesis; Histone acetyltransferase
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
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APA (6th Edition):
Dharampuriya, P. (2017). Role of epigenetics in hematopoietic stem cell development. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/23717
Chicago Manual of Style (16th Edition):
Dharampuriya, Priyanka. “Role of epigenetics in hematopoietic stem cell development.” 2017. Masters Thesis, Boston University. Accessed March 04, 2021.
http://hdl.handle.net/2144/23717.
MLA Handbook (7th Edition):
Dharampuriya, Priyanka. “Role of epigenetics in hematopoietic stem cell development.” 2017. Web. 04 Mar 2021.
Vancouver:
Dharampuriya P. Role of epigenetics in hematopoietic stem cell development. [Internet] [Masters thesis]. Boston University; 2017. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/2144/23717.
Council of Science Editors:
Dharampuriya P. Role of epigenetics in hematopoietic stem cell development. [Masters Thesis]. Boston University; 2017. Available from: http://hdl.handle.net/2144/23717

Columbia University
26.
Corrigan, David Joseph.
Differential Roles of PRDM16 Isoforms in Normal and Malignant Hematopoiesis.
Degree: 2018, Columbia University
URL: https://doi.org/10.7916/D8S19K1D
► PRDM16 is a transcriptional co-regulator that is highly expressed in HSCs and required for their maintenance. It is also involved in translocations in acute myeloid…
(more)
▼ PRDM16 is a transcriptional co-regulator that is highly expressed in HSCs and required for their maintenance. It is also involved in translocations in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and T-cell acute lymphoblastic leukemia. Prdm16 is expressed as both full-length (f Prdm16) and short-length (s-Prdm16) isoforms, the latter lacking an N-terminal PR domain homologous to SET methyltransferase domains. The roles of both isoforms in normal and malignant hematopoiesis are unclear. In chromosomal rearrangements involving PRDM16, the PR domain is deleted. Furthermore, overexpression of s-Prdm16, but not f-Prdm16, can cause leukemia in a p53-/- background predisposed to malignancy. Based on this, s-Prdm16 has been proposed as an oncogene whereas f-Prdm16 has been suggested to possess tumor suppressor activity.
The aim of this thesis was to more clearly elucidate the role of each Prdm16 isoform in normal and malignant hematopoiesis. We first showed that Prdm16 is essential for adult HSC maintenance using a conditional deletion mouse model specific for hematopoietic cells, as previous findings using an embryonic-lethal global Prdm16-/- mouse demonstrated this only in fetal liver. We then found, using a specific f-Prdm16-/- mouse model, that full-length Prdm16 is essential for HSC maintenance and induces multiple genes involved in GTPase signaling and represses inflammation. Based on a comparison of Prdm16-/- HSCs lacking both isoforms, and f-Prdm16-/- HSCs which express s-Prdm16, we were able to infer some hematopoietic properties of s-Prdm16 – namely that this isoform induces inflammatory gene expression and supports development of a Lineage-Sca1+cKit- lymphoid progenitor distinct from CLPs which predominantly differentiates into marginal zone B cells. s-Prdm16 expression alone, however, was not sufficient to maintain HSCs.
We used a mouse model of human MLL-AF9 leukemia and found that leukemia derived from Prdm16-deficient HSCs had extended latency, although expression of Prdm16 decreases during MLL-AF9 transformation and is undetectable in ex vivo leukemic cells. Forced expression of f-Prdm16 in these cells further extended leukemic latency, while forced expression of s-Prdm16 shortened latency. Gene expression profiling using RNAseq indicated that forced expression of f-Prdm16 resulted in altered respiratory metabolism of MLL-AF9 cells, whereas expression of s-Prdm16 induced a strong inflammatory gene signature, comparable to that seen in HSCs expressing only s-Prdm16. Several inflammatory cytokines and chemokines induced by s-Prdm16 are associated with MDS and with a worse prognosis in human AML. Furthermore, leukemia expressing s-Prdm16 had an elevated number of cells with abnormal nuclei, characteristic of dysplasia.
Finally, we performed an analysis of PRDM16 in human AML from the publically-available Cancer Genome Atlas dataset, containing clinical and gene expression data for 179 cases of AML. PRDM16 expression negatively correlated with overall survival, both in the…
Subjects/Keywords: Immunology; Microbiology; Hematopoiesis; Genetic transcription – Regulation; Proteins
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Corrigan, D. J. (2018). Differential Roles of PRDM16 Isoforms in Normal and Malignant Hematopoiesis. (Doctoral Dissertation). Columbia University. Retrieved from https://doi.org/10.7916/D8S19K1D
Chicago Manual of Style (16th Edition):
Corrigan, David Joseph. “Differential Roles of PRDM16 Isoforms in Normal and Malignant Hematopoiesis.” 2018. Doctoral Dissertation, Columbia University. Accessed March 04, 2021.
https://doi.org/10.7916/D8S19K1D.
MLA Handbook (7th Edition):
Corrigan, David Joseph. “Differential Roles of PRDM16 Isoforms in Normal and Malignant Hematopoiesis.” 2018. Web. 04 Mar 2021.
Vancouver:
Corrigan DJ. Differential Roles of PRDM16 Isoforms in Normal and Malignant Hematopoiesis. [Internet] [Doctoral dissertation]. Columbia University; 2018. [cited 2021 Mar 04].
Available from: https://doi.org/10.7916/D8S19K1D.
Council of Science Editors:
Corrigan DJ. Differential Roles of PRDM16 Isoforms in Normal and Malignant Hematopoiesis. [Doctoral Dissertation]. Columbia University; 2018. Available from: https://doi.org/10.7916/D8S19K1D

Columbia University
27.
Mumau, Melanie.
The ins and outs of stem cells: regulation of cell fate in embryonic stem cells and hematopoiesis.
Degree: 2018, Columbia University
URL: https://doi.org/10.7916/D8WD5BGJ
► The decisions stem cells make impact both the development of adult vertebrates and systems within the body that require cellular replenishment to sustain life. Regardless…
(more)
▼ The decisions stem cells make impact both the development of adult vertebrates and systems within the body that require cellular replenishment to sustain life. Regardless whether a stem cell remains quiescent, divides, differentiates, or undergoes apoptosis—these processes are precisely controlled by internal gene regulatory networks that are instructed by external stimuli. The exact mechanisms governing stem cell fate are not completely understood.
These studies explore new ways in which cell fate is mediated. Through a study of mitochondrial content in human embryonic stem cells (hESCs) and their differentiated progeny, we discovered differences in mitochondrial morphologies. Mitochondria began as elongated and networked structures in self-renewing conditions and changed their shape after differentiation. The addition of external growth factors that direct hESCs toward the definitive endoderm (DE) lineage promoted mitochondrial fragmentation, which was mediated by the mitochondrial fission machinery. Globular, punctate mitochondria were observed prior to the induction of the DE-specific transcriptional program. Differentiation of hESCs to other lineages did not result in any mitochondrial shape changes. Thus, mitochondrial fission in differentiating hESCs, an internal cellular process, is induced by DE-inducing external stimuli, an effect that was lineage specific.
In a second study, we investigated the role of the splenic environment in the development of the blood system—during hematopoiesis. The spleen made a distinct contribution to hematopoiesis, a process predominantly attributed to the bone marrow. We discovered a previously unidentified population of cells, uniquely represented in the mouse spleen that could develop into erythrocytes, monocytes, granulocytes, and platelets. These multipotent progenitors of the spleen (MPPS) expressed higher levels of the transcription factor, NR4A1 compared to their bone marrow counterparts and relied on NR4A1 expression to direct their cell fate. The activation of NR4A1 in MPPS biased their production of monocytes and granulocytes in vitro whereas NR4A1-deficient MPPS over-produced erythroid lineage cells in vivo. Together, these data suggest the splenic niche supports distinct myeloid differentiation programs of multi-lineage progenitors cells.
Both studies identify new mechanisms by which external stimuli regulate internal mechanisms of cell fate. These insights provide a better understanding of stem and progenitor cell differentiation that have the potential to impact cellular replacement therapies.
Subjects/Keywords: Immunology; Hematopoiesis; Embryonic stem cells; Cytology
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Mumau, M. (2018). The ins and outs of stem cells: regulation of cell fate in embryonic stem cells and hematopoiesis. (Doctoral Dissertation). Columbia University. Retrieved from https://doi.org/10.7916/D8WD5BGJ
Chicago Manual of Style (16th Edition):
Mumau, Melanie. “The ins and outs of stem cells: regulation of cell fate in embryonic stem cells and hematopoiesis.” 2018. Doctoral Dissertation, Columbia University. Accessed March 04, 2021.
https://doi.org/10.7916/D8WD5BGJ.
MLA Handbook (7th Edition):
Mumau, Melanie. “The ins and outs of stem cells: regulation of cell fate in embryonic stem cells and hematopoiesis.” 2018. Web. 04 Mar 2021.
Vancouver:
Mumau M. The ins and outs of stem cells: regulation of cell fate in embryonic stem cells and hematopoiesis. [Internet] [Doctoral dissertation]. Columbia University; 2018. [cited 2021 Mar 04].
Available from: https://doi.org/10.7916/D8WD5BGJ.
Council of Science Editors:
Mumau M. The ins and outs of stem cells: regulation of cell fate in embryonic stem cells and hematopoiesis. [Doctoral Dissertation]. Columbia University; 2018. Available from: https://doi.org/10.7916/D8WD5BGJ

University of Oxford
28.
Bonkhofer, Florian.
Identification of novel Runx1 targets involved in HSC development.
Degree: PhD, 2017, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:4badf9f4-f796-4063-8176-dd57644fd811
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.740861
► Haematopoietic stem and progenitor cells (HSPCs) are de novo generated within in the ventral aspects of the embryonic dorsal aorta (DA). Cells of this haemogenic…
(more)
▼ Haematopoietic stem and progenitor cells (HSPCs) are de novo generated within in the ventral aspects of the embryonic dorsal aorta (DA). Cells of this haemogenic endothelium (HE) will eventually undergo an endothelial to haematopoietic transition (EHT) that involves cell budding out of the aortic wall. Despite the detailed description of the cellular events, the exact haemogenic lineage path and the underlying molecular mechanism that establish full haematopoietic competence are still not entirely understood. The transcription factor Runx1 is critical for the emergence of HSPCs and shows expression in the zebrafish HE as early as 24 hpf. To facilitate a detailed analysis of the transient HE population I generated a TgBAC(runx1P2:Citrine) reporter line under the control of the endogenous runx1 promoter on a bacterial artificial chromosome (BAC). Double-transgenic reporter lines for runx1 and the endothelial marker kdrl allowed us to isolate specifically cells of the DA away from the whole endothelial population, which could be further sub-divided into HE and non-haemogenic cells. Genomewide expression analysis within the respective tissues and upon Runx1 loss of function enabled the identification of HE-specific Runx1-regulated genes. Hereby, the gfi1ab gene appeared as the functional homologue of the murine Gfi1. I show that in zebrafish, EHT is orchestrated through a conserved Runx1-Gfi1-Lsd1 axis. The cellular functions of the remaining Runx1 targets imply that maturation into fully functional HSCs depends on epigenetic regulation due to the up-regulation of de novo DNAmethyltransferases, as well as on factors that allow the developing HSCs to respond to extrinsic cues from haematopoietic niches. Lastly, it became evident that the early HE expresses dll4 at similar levels to the rest of the aortic endothelium, indicating a common lineage path. In the absence of RUNX1 the HE remains essentially arterial and persists as an integrated part of the DA.
Subjects/Keywords: 610; Medical sciences – Research; Runx1; Hematopoiesis
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Bonkhofer, F. (2017). Identification of novel Runx1 targets involved in HSC development. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:4badf9f4-f796-4063-8176-dd57644fd811 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.740861
Chicago Manual of Style (16th Edition):
Bonkhofer, Florian. “Identification of novel Runx1 targets involved in HSC development.” 2017. Doctoral Dissertation, University of Oxford. Accessed March 04, 2021.
http://ora.ox.ac.uk/objects/uuid:4badf9f4-f796-4063-8176-dd57644fd811 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.740861.
MLA Handbook (7th Edition):
Bonkhofer, Florian. “Identification of novel Runx1 targets involved in HSC development.” 2017. Web. 04 Mar 2021.
Vancouver:
Bonkhofer F. Identification of novel Runx1 targets involved in HSC development. [Internet] [Doctoral dissertation]. University of Oxford; 2017. [cited 2021 Mar 04].
Available from: http://ora.ox.ac.uk/objects/uuid:4badf9f4-f796-4063-8176-dd57644fd811 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.740861.
Council of Science Editors:
Bonkhofer F. Identification of novel Runx1 targets involved in HSC development. [Doctoral Dissertation]. University of Oxford; 2017. Available from: http://ora.ox.ac.uk/objects/uuid:4badf9f4-f796-4063-8176-dd57644fd811 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.740861

Hong Kong University of Science and Technology
29.
Wu, Yi.
Establishment of a genetic system for myeloid cell fate mapping in zebrafish.
Degree: 2014, Hong Kong University of Science and Technology
URL: http://repository.ust.hk/ir/Record/1783.1-86325
;
https://doi.org/10.14711/thesis-b1334218
;
http://repository.ust.hk/ir/bitstream/1783.1-86325/1/th_redirect.html
► Myeloid cells, composed of granulocytes and monocytes, have very significant roles in the immune response and tissue remodeling. All myeloid cells are derived from hematopoiesis.…
(more)
▼ Myeloid cells, composed of granulocytes and monocytes, have very significant roles in the immune response and tissue remodeling. All myeloid cells are derived from hematopoiesis. Similar to mammals, zebrafish hematopoiesis consists of two waves, primitive hematopoiesis and definitive hematopoiesis. These two waves take place in different locations at different time course. Primitive hematopoiesis is a transient wave and takes place in the early stage. It mainly gives rise to myeloid cells and erythrocytes. Definitive hematopoiesis can generate hematopoietic stem cells, which can give rise to all kinds of cells of blood lineage including myeloid cells, erythrocytes and lymphocytes. The macrophages generated by hematopoiesis will migrate into different organs to become tissue resident macrophages, such as microglia in the brain. The origin of tissue resident macrophages is an interesting research field to investigate. Myeloid cell fate mapping in mice has been conducted by many groups to figure out which hematopoietic wave tissue resident macrophages are derived from. However, there has not been a consensus in this issue yet, and it still remains an open question. We tried to label different waves of myeloid cells in zebrafish embryos and observe their distribution in the adult organs. Two transgenic lines Tg(coro1a:CreER T2) and Tg(coro1a:LOXP-DsRedx-LOXP-eGFP) were generated, and this Cre-lopx system can permanently convert Dsred positive myeloid cells into GFP positive myeloid cells. Taking the advantage of model system zebrafish, we can label one wave of myeloid cells with different methods. Preliminary data show that controlling the time of labelling using Tg(coro1a:CreER T2) line or controlling the location of labelling using (hsp70:mCherry-T2a-CreERT2) #12 line with a local IR laser induction may effectively label myeloid cells at different time course or in different locations. Therefore, it is shown this system can be applied in the myeloid cell fate mapping experiment in zebrafish.
Subjects/Keywords: Hematopoiesis
; Zebra danio
; Genetics
; Stem cells
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Wu, Y. (2014). Establishment of a genetic system for myeloid cell fate mapping in zebrafish. (Thesis). Hong Kong University of Science and Technology. Retrieved from http://repository.ust.hk/ir/Record/1783.1-86325 ; https://doi.org/10.14711/thesis-b1334218 ; http://repository.ust.hk/ir/bitstream/1783.1-86325/1/th_redirect.html
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Wu, Yi. “Establishment of a genetic system for myeloid cell fate mapping in zebrafish.” 2014. Thesis, Hong Kong University of Science and Technology. Accessed March 04, 2021.
http://repository.ust.hk/ir/Record/1783.1-86325 ; https://doi.org/10.14711/thesis-b1334218 ; http://repository.ust.hk/ir/bitstream/1783.1-86325/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Wu, Yi. “Establishment of a genetic system for myeloid cell fate mapping in zebrafish.” 2014. Web. 04 Mar 2021.
Vancouver:
Wu Y. Establishment of a genetic system for myeloid cell fate mapping in zebrafish. [Internet] [Thesis]. Hong Kong University of Science and Technology; 2014. [cited 2021 Mar 04].
Available from: http://repository.ust.hk/ir/Record/1783.1-86325 ; https://doi.org/10.14711/thesis-b1334218 ; http://repository.ust.hk/ir/bitstream/1783.1-86325/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Wu Y. Establishment of a genetic system for myeloid cell fate mapping in zebrafish. [Thesis]. Hong Kong University of Science and Technology; 2014. Available from: http://repository.ust.hk/ir/Record/1783.1-86325 ; https://doi.org/10.14711/thesis-b1334218 ; http://repository.ust.hk/ir/bitstream/1783.1-86325/1/th_redirect.html
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Notre Dame
30.
Dawn Weseli Hopkins.
The Genetic Control of Hematopoietic Progenitor Fate in
<i>Drosophila</i></h1>.
Degree: Biological Sciences, 2014, University of Notre Dame
URL: https://curate.nd.edu/show/ng451g07s8m
► Drosophila has emerged as an important model system in the examination of the hematopoietic process owing to the conserved nature of many of the…
(more)
▼ Drosophila has emerged as an important model
system in the examination of the hematopoietic process owing to the
conserved nature of many of the transcription factors and signaling
pathways utilized to produce blood cells. Mirroring vertebrate
hematopoiesis, Drosophila generate hemocytes in a distinct spatial
temporal course. The focus of the following study concerns the
definitive wave of
hematopoiesis, which occurs in the lymph gland
(LG). Through microarray analysis, bag-of-marbles (bam) was found
to be transcriptionally active in the LG. Furthermore, Bam was
expressed in both the niche cells of the posterior signaling center
(PSC) and the progenitors of the medullary zone (MZ). The
progenitor cells of bam mutant LGs prematurely differentiate into
all three hemocyte types. Additionally, the PSC number is
dramatically increased and the cells are dispersed throughout the
primary LG tissue. These two distinct phenotypes demonstrate that
bam has cell-autonomous functions in these separate regions of the
LG. In order to further define the function of bam, a sensitized
third chromosome deficiency screen was conducted implementing one
null copy of bam (bam∆86) and the lamellocyte specific enhancer
reporter, MSNF9mcherry. Through continued screening, two genes were
uncovered that displayed a bam-dependent lamellocyte suppression,
Rab11 and qin. An additional three genes previously unknown to
function in
hematopoiesis were found to suppress lamellocyte
differentiation in a bam-independent manner (msps, cct1, and
ChaVAchT). Further investigation of the interaction between Bam and
Qin revealed co-localization of the two proteins in early third
instar LGs and a significant reduction of hematopoietic progenitors
in LGs heterozygous for both bam∆86 and qine03728. Forced
expression of the C-terminal domain of qin with a MZ-specific
driver caused significant expansion of the MZ, similar to the
full-length construct and was able to rescue the reduced LG and MZ
size characteristic of qin mutants, highlighting the importance of
the Tudor domains located in this fragment. Lastly, qin and bam may
be functioning through an epigenetic mechanism as the nuclear
localization of HP1a (Heterochromatin protein 1a) is altered in
heterozygous mutant LGs. Together, these findings have provided
important insights into the genetic control of hematopoietic
progenitor fate in Drosophila.
Advisors/Committee Members: Dr. Kevin Vaughan, Committee Member, Dr. Robert Schulz, Committee Chair, Dr. Joseph OTousa, Committee Member, Dr. David Hyde, Committee Member.
Subjects/Keywords: Drosophila; genetics; bag-of-margles; hematopoiesis
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hopkins, D. W. (2014). The Genetic Control of Hematopoietic Progenitor Fate in
<i>Drosophila</i></h1>. (Thesis). University of Notre Dame. Retrieved from https://curate.nd.edu/show/ng451g07s8m
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Hopkins, Dawn Weseli. “The Genetic Control of Hematopoietic Progenitor Fate in
<i>Drosophila</i></h1>.” 2014. Thesis, University of Notre Dame. Accessed March 04, 2021.
https://curate.nd.edu/show/ng451g07s8m.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Hopkins, Dawn Weseli. “The Genetic Control of Hematopoietic Progenitor Fate in
<i>Drosophila</i></h1>.” 2014. Web. 04 Mar 2021.
Vancouver:
Hopkins DW. The Genetic Control of Hematopoietic Progenitor Fate in
<i>Drosophila</i></h1>. [Internet] [Thesis]. University of Notre Dame; 2014. [cited 2021 Mar 04].
Available from: https://curate.nd.edu/show/ng451g07s8m.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Hopkins DW. The Genetic Control of Hematopoietic Progenitor Fate in
<i>Drosophila</i></h1>. [Thesis]. University of Notre Dame; 2014. Available from: https://curate.nd.edu/show/ng451g07s8m
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
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