The goal of this proposal is to further characterize the functional activities of MEF, a member of the ETS family of transcription factors, in hematopoietic cells. We have identified an essential role of MEF in innate immunity, and in regulating hematopoietic stem cell (HSC) biology. Our focus now is to more completely define the role of MEF in controlling HSC self-renewal, characterize the basis for its transforming properties, and understand the mechanistic bases for its cell cycle promoting effects. To accomplish this, we propose to further define the role of MEF in regulating quiescence and the chemo- sensitivity of hematopoietic cells, by re-introducing wild type and mutant forms of MEF into MEF null HSCs, and by examining how the mechanisms invoked by MEF and by p53 interact in this process. We will further define how known cell cycle regulatory genes, such as p21, modulate the effects of MEF on HSC self-renewal processes. We will also further define the role of MEF in malignant transformation by defining its importance in the transforming properties of known oncogenes (such as H-RasV12) using mouse embryonic fibroblasts. Furthermore, we will define the role MEF plays in regulating p53 levels and cellular senescence, and by crossing MEF null mice with p53 null mice, will define the relationship between its cell cycle promoting and its transforming effects. To define how these effects are regulated in the cell, we will examine phosphorylation site mutant forms of MEF in different biological assays to understand how cellular kinases (e.g. the ERK2 MAP kinase) affect the function of MEF. Lastly, we will utilize transcript profiling to define which MEF target genes are essential for its effects on cellular quiescence, senescence, and transformation. By providing valuable insight into these critical issues, we will better understand stem cell biology and the pathogenesis of human cancer. Project Narrative: The absence of MEF leads to enhanced HSC quiescence and relative resistance to chemotherapy. In this proposal, we will define the mechanisms underlying normal hematopoietic stem cell quiescence and self-renewal, and will compare them to the mechanisms controlling these properties in transformed cells. We hope that the information gained can be exploited to improve the therapeutic index of current cancer treatments and devise new therapeutic approaches.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hematopoiesis Study Section (HP)
Program Officer
Bishop, Terry Rogers
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Asai, Takashi; Hatlen, Megan A; Lossos, Chen et al. (2016) Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms. Sci Rep 6:22760
Xu, Haiming; Menendez, Silvia; Schlegelberger, Brigitte et al. (2012) Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13-driven mouse model. Blood 120:3089-97
Liu, Yan; Liu, Fan; Yu, Hao et al. (2012) Akt phosphorylates the transcriptional repressor bmi1 to block its effects on the tumor-suppressing ink4a-arf locus. Sci Signal 5:ra77
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Huang, Gang; Zhao, Xinghui; Wang, Lan et al. (2011) The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations. Blood 118:6544-52
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