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Karolinska Institute

1. Scharenberg, Christian. The mutational landscape and microenvironment in myelodysplastic syndromes with deletion of chromosome 5q .

Degree: 2018, Karolinska Institute

Myelodysplastic Syndromes (MDS) with deletion of chromosome 5q (del(5q) are malignant bone marrow disorders characterized by macrocytic anemia, chronic transfusion dependency and an increased risk of progression to acute myeloid leukemia. A high proportion of patients with lower-risk del(5q) myelodysplastic syndromes will respond to lenalidomide treatment, but more than 40% of patients have progressed to acute leukemia five years after starting treatment. In this thesis, we characterized the rare MDS stem cells and bone marrow microenvironment of low-risk del(5q) MDS and studied whether certain somatic mutations are associated with disease progression. We isolated stem and progenitor cells from lower-risk MDS patients by flow cytometric cell sorting and characterized these populations functionally and molecularly. By fluorescence in situ hybridisation we found the distinct stem and progenitor cells to be clonally involved. This allowed us to determine that the hierarchical organization in del(5q) MDS is similar to that of healthy bone marrow. Exploiting the fact that the vast majority of MDS cases harbour somatic mutations we employed a fate-mapping approach and observed that all somatic mutations found in the bulk bone marrow could be traced back to MDS stem cells. We observed that the del(5q) abnormality preceded the acquisition of additional mutations. Hypothesizing that the acquisition of certain somatic mutations might help explain progression in del(5q) MDS, we used a cohort of 35 longitudinally sampled patients to study whether certain mutations are associated with disease progression. Overall, the mutational landscape in a pure del(5q) cohort differed from low-risk MDS in general. Thirteen patients progressed to high-risk MDS or leukemia at a median of 85 months after diagnosis. We found progression to be associated with the detection of a limited subset of new mutations, i.e., TP53, TET2, and RUNX1. Of nine patients who progressed to AML, all were treated with lenalidomide and 7 were found to have mutations in TP53, which were present in the earliest sample in one case and acquired in the remaining six cases. Importantly, the new mutations were detected well before signs of clinical progression occurred. Whether or not the microenvironment is perturbed or merely a bystander has been a heavily contentious issue in the literature - not only for MDS but for myeloid diseases in general. Comparing gene expression in cultured mesenchymal stromal cells from del(5q) and normal patients demonstrated no significant differences. Bone marrow biopsies in del(5q) MDS patients before and during lenalidomide treatment revealed significantly higher microvessel density (MVD) in del(5q) MDS compared to normal controls. In all patients analyzed, MVD decreased upon lenalidomide treatment, increasing again upon therapeutic failure. Analysis of staining patterns did not reveal quantitative differences in the expression of previously associated MSC markers between del(5q) MDS and…

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APA (6th Edition):

Scharenberg, C. (2018). The mutational landscape and microenvironment in myelodysplastic syndromes with deletion of chromosome 5q . (Thesis). Karolinska Institute. Retrieved from http://hdl.handle.net/10616/46191

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):

Scharenberg, Christian. “The mutational landscape and microenvironment in myelodysplastic syndromes with deletion of chromosome 5q .” 2018. Thesis, Karolinska Institute. Accessed February 18, 2018. http://hdl.handle.net/10616/46191.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Scharenberg, Christian. “The mutational landscape and microenvironment in myelodysplastic syndromes with deletion of chromosome 5q .” 2018. Web. 18 Feb 2018.

Vancouver:

Scharenberg C. The mutational landscape and microenvironment in myelodysplastic syndromes with deletion of chromosome 5q . [Internet] [Thesis]. Karolinska Institute; 2018. [cited 2018 Feb 18]. Available from: http://hdl.handle.net/10616/46191.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Scharenberg C. The mutational landscape and microenvironment in myelodysplastic syndromes with deletion of chromosome 5q . [Thesis]. Karolinska Institute; 2018. Available from: http://hdl.handle.net/10616/46191

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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