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|Title:||RETENTION OF RUNX1-INSUFFICIENT CD41+ PLATELET-BIASED HEMATOPOIETIC STEM CELLS IN NICHE BY ADDITIONAL GENETIC MUTATIONS FACILITATES MYELOID LEUKEMOGENESIS||Authors:||MOK MENG HUANG, MICHELLE||ORCID iD:||orcid.org/0000-0001-7030-266X||Keywords:||CD41, MEGAKARYOCYTE-BIAS, HEMATOPOIETIC STEM CELLS, LEUKEMIA, RUNX1||Issue Date:||3-Jul-2021||Citation:||MOK MENG HUANG, MICHELLE (2021-07-03). RETENTION OF RUNX1-INSUFFICIENT CD41+ PLATELET-BIASED HEMATOPOIETIC STEM CELLS IN NICHE BY ADDITIONAL GENETIC MUTATIONS FACILITATES MYELOID LEUKEMOGENESIS. ScholarBank@NUS Repository.||Abstract:||RUNX1 is among the most frequently mutated genes in human myeloid leukemia. RUNX1 alterations per se, though being leukemia-prone, are insufficient to cause overt leukemia due to a niche interaction defect. Additional genetic changes in NRAS and MLL5 have been observed in RUNX1 leukemia, yet the molecular basis for this synergism remains elusive. Here we report that restoration of niche interaction of HSCs is facilitated by such additional genetic changes in myeloid leukemogenesis. Flow cytometry analysis demonstrated that concurrent genetic alterations lead to the propagation of CD41+ platelet-biased HSCs which may serve as a cell-of-origin for myeloid leukemia. Mechanistically, transcriptional repression of DNA damage-inducing LINE-1 retrotransposon by Runx1 and CTCF-Stat5 mediated by niche-derived thrombopoietin is attenuated in the Runx1 mutant HSCs, but restored by the acquisition of the second hits. These findings on the niche-related mechanism would provide deeper insights into myeloid leukemogenesis and may lead to novel therapeutics.||URI:||https://scholarbank.nus.edu.sg/handle/10635/212676|
|Appears in Collections:||Ph.D Theses (Restricted)|
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