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Characterization of RUNX1 function in hematopoiesis /


RUNX1 or runt-related transcription factor 1 is a transcription factor in the RUNX family of proteins. This family is composed of RUNX1, RUNX2, and RUNX3--all of which contain the runt homology domain, which mediates interaction with DNA and other transcriptional co-factors. RUNX1 has garnered much attention over the past decades primarily because its disruption has been associated with a variety of human diseases and malignancies. Several chromosomal translocations in leukemias involve RUNX1. The most famous one is between chromosomes 8 and 21 resulting in the RUNX1-ETO fusion and leads to acute myeloid leukemia. Since then, RUNX1 mutations have been found in acute lymphoid leukemia, myelodysplastic syndrome, myeloproliferative neoplasm, familial platelet disease, and others. Although RUNX1 has been a major focus in the field of hematology, many of the molecular and cellular mechanisms of how RUNX1 disruption leads to disease remain unknown. Uncovering these mechanisms will result in a better understanding of these diseases and may lead to meaningful therapies. As a transcription factor, RUNX1 primarily exerts its functions by regulating target genes. This dissertation explores how these target genes ultimately facilitate RUNX1 functions in hematopoiesis and in hematopoietic stem and progenitor cells (HSPCs). We first focus on Hmga2 or high mobility group AT-hook 2, which was found to be up-regulated in RUNX1 loss-of- function HSPCs. Hmga2 is an established oncogene and has roles in inducing cellular proliferation. Notably, Hmga2 was found to contribute to myeloid progenitor cell expansion, which is a main characteristic of RUNX1 loss-of -function. Next, we analyzed differential gene expression data from wildtype and RUNX1 loss-of-function HSPCs and determined that these genes are involved in pathways associated with cell-to-cell interaction and signaling. Upon further examination, we discovered that RUNX1 loss-of -function mice exhibit hypersensitivity to HSPC mobilization regimens. Finally, we focus on another RUNX1 target gene known as Gimap4 or GTPase of the immunity- associated protein 4 and confirm that up-regulation of Gimap4 contributes to HSPC expansion, a finding also found in RUNX1 loss-of-function mice. Together, these studies provide critical insight in the role of RUNX1 in hematopoiesis and blood-related diseases, and offer additional avenues for therapies for these diseases

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