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Title: Identification of additional genetic alterations in RUNX1 related leukemias
Keywords: AML1/ EVI5/ retroviral insertional mutagenesis/ leukemia stem cell/ niche/ CXCR4
Issue Date: 8-Apr-2008
Citation: BINDYA JACOB (2008-04-08). Identification of additional genetic alterations in RUNX1 related leukemias. ScholarBank@NUS Repository.
Abstract: The RUNX1/AML1 gene is essential for the generation of hematopoietic stem cells (HSC) and is the most frequently mutated gene in human leukemia. Conditional deletion of Runx1 in adult mice results in an increase of HSC which serve as the target cell pool for leukemia; however, Runx1-/- mice do not develop spontaneous leukemia, suggesting that additional genetic changes are required for the leukemia development. Here we show that maintenance of Runx1-/- stem cells is compromised due to the defect in interaction between HSC and niche, resulting in progressively declining contribution to hematopoiesis. Retroviral insertional mutagenesis revealed the overexpression of Evi5 as a cooperating genetic alteration which prevents this Runx1-/- HSC exhaustion. EVI5 overexpression rescued niche interaction defects and maintained an expanded pool of Runx1 deficient HSC in vitro and in vivo. Stem cell exhaustion after transient expansion and its rescue seem to be potentially widespread fundamental mechanism in cancer development.
Appears in Collections:Ph.D Theses (Open)

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