FLT3: Role and regulation in HSC

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Signaling stimulated through the FLT3 receptor by its ligand, FL, appears to play an important role in hematopoiesis. FL synergizes with other factors to enhance the proliferation/maintenance of human lymphohematopoietic stem-progenitor cells (HSC) in vitro. FL is part of most cocktails of cytokines and growth factors being used to culture human HSC ex vivo. FL also stimulates dendritic, B progenitor, and NK cell development. However, it is still unclear at this time whether or not FLT3 plays a role in proliferation, antiapoptosis, and differentiation of high quality HSC and/or low quality HSC. We have developed very potent, specific small molecule inhibitors ofFLT3 tyrosine kinase activity. Utilizing these inhibitors we can probe FLT3 function in different cell populations by shutting it offwhile still allowing other normal cellular processes to take place. These reagents might, in the future, be used to complement the cellular approaches to SAA and GVHD taking place in Projects 1 and 4. Within this project we will probe the biological function of FLT3 in both low and high quality HSC. For an identified set of candidate targets of FLT3 signaling, we will define the downstream gene expression pattern that is dependent on FLT3 activation in high and low quality HSC. Finally, FLT3 regulation in normal HSC will be studied in an attempt to understand why FLT3 is overexpressed in so many leukemias. Specific Aim 1: Define the role of FLT3-mediated signal transduction in high quality HSC and low quality HSC. Specific Aim 2: Determine the candidate gene expression profile dependent on FLT3 signaling in high and low quality HSC. Specific Aim 3: Identify enhancers and transcription factors which regulate the FLT3 gene in HSC.