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1. Purushe, Janaki. MLL4-Menin Complex Inhibition Promotes Central Memory In CD8 CAR-T Cells.
Degree: PhD, 2018, Temple University
Infectious Disease & Immunity
CAR-T cell immunotherapy is a highly efficacious treatment for CD19-positive hematological malignancies, however, some patients are non-responsive for reasons that are not well understood. Clinical efficacy has been correlated with long-term persistence, a propensity that can be predicted by the differentiation state of transplanted cells. Despite this, decades-old methods for expanding T cells have not been updated to prevent the deleterious effects of excessive differentiation in CAR-T cells. Uncoupling proliferation and differentiation is a long-held goal in the field of immunotherapy with both cytokines and pharmacological approaches being implemented to dissociate these parallel processes. Histone methyltransferases rewire transcriptional programs in T cells and simultaneously regulate multitudes of genes, making them attractive targets for modifying the proliferation-differentiation axis. Despite this, only a handful of studies have examined their role in regulating the transcriptional programs of human CD8+ T cells. MLL4 (encoded by KMT2B) belongs to the six-member group of MLL histone methyltransferases. MLL1, a paralog of MLL4, has been implicated in regulating the maintenance of IL-4 and GATA-3 expression in TH2 CD4 memory T cell populations, however the function of MLL4 in human CD8+ T cells is unknown. We report a critical role for MLL4 in the proliferation and differentiation of CD8+ T cells. CRISPR-Cas9-editing of MLL4 uncoupled the processes of proliferation and differentiation, increasing proliferation but maintaining central memory T cell (TCM)-like populations, allowing for the production of increased numbers of TCM-like CD62L+CD45RO+ cells. Pharmacologically inhibiting the MLL4-Menin complex with MI-2 during T cell expansion enriched the frequency of minimally differentiated TCM-like CD8+ T cells. TCM-associated CD62L, CCR7, CD122 and CD127 surface markers were upregulated and early memory-associated transcription factor TCF7, LEF1, EOMES, and FOXP1 transcripts were increased. CD8+ CAR-T cells expanded in the presence of MI-2 responded earlier, while improving both tumor burden and survival in a NSG xenograft model of human leukemia. This finding has important translational impact in improving the persistence and proliferative capacity of CD8+ CAR-T cells.
Temple University – ThesesAdvisors/Committee Members: Zhang, Yi;, Issa, Jean-Pierre, Monestier, Marc, Gallucci, Stefania, Soboloff, Jonathan;.
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APA (6th Edition):
Purushe, J. (2018). MLL4-Menin Complex Inhibition Promotes Central Memory In CD8 CAR-T Cells. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,489872
Chicago Manual of Style (16th Edition):
Purushe, Janaki. “MLL4-Menin Complex Inhibition Promotes Central Memory In CD8 CAR-T Cells.” 2018. Doctoral Dissertation, Temple University. Accessed February 20, 2019. http://digital.library.temple.edu/u?/p245801coll10,489872.
MLA Handbook (7th Edition):
Purushe, Janaki. “MLL4-Menin Complex Inhibition Promotes Central Memory In CD8 CAR-T Cells.” 2018. Web. 20 Feb 2019.
Purushe J. MLL4-Menin Complex Inhibition Promotes Central Memory In CD8 CAR-T Cells. [Internet] [Doctoral dissertation]. Temple University; 2018. [cited 2019 Feb 20]. Available from: http://digital.library.temple.edu/u?/p245801coll10,489872.
Council of Science Editors:
Purushe J. MLL4-Menin Complex Inhibition Promotes Central Memory In CD8 CAR-T Cells. [Doctoral Dissertation]. Temple University; 2018. Available from: http://digital.library.temple.edu/u?/p245801coll10,489872