Inappropriate expression of the TAL1 gene (formerly known as SCL and TCL5) is the most frequent gain-of-function mutation observed in T-cell acute lymphoblastic leukemia. TAL1, a member of the basic helix-loop- helix family of transcription factors, has also been shown through gene targeting studies to have an essential role in the development of all hematopoietic lineages. Although these observations suggest the gene must regulate critical processes in cell growth, little is known about either its normal actions or how its misexpression contributes to leukemogenesis. We have established the locations and cell types in which TAL1 protein is made in murine and avian embryonic development, demonstrated that Tal1 RNA, protein, DNA-binding activity are regulated by erythropoietin in murine erythroid progenitors, defined several of the sites and functional consequences of Tal1 protein phosphorylation in erythroid cells, and determined that Tal1 can cooperate with members of another class of T-cell oncoproteins with which it is coexpressed in leukemias in altering the proliferation and survival of immortalized mouse fibroblasts. This renewal application outlines a series of experiments aimed at elucidating its specific actions in hematopoietic cells in which it is expressed physiologically and the mechanism by which TAL1 alters the proliferation and survival of cells in which it is misexpressed. The first specific aim is to determine whether TAL1 expression or activity is subject to cell-cycle regulation. Tal1 abundance, DNA-binding activity, and phosphorylation will be examined in erythropoietin-dependent erythroid progenitors synchronized in different phases of the cell cycle. The second specific aim is to elucidate the functions of TAL1 in normal growth control. A DNA binding-defective Tal1 mutant will be inducibly expressed in an erythropoietin-dependent erythroid cell line and its specific effects on proliferation, survival, and differentiation determined. The third specific aim is to elucidate the mechanism by which misexpression of TAL1 alters growth control. The basis for the altered growth and survival of NIH 3T3 cells engineered to coexpress TAL1 with another T- cell oncoprotein, LMO1, will be determined, and candidates to modulate or mediate these actions will be examined. The results of these studies will advance basic understanding of hematopoietic differentiation and provide insights into mechanisms of leukemogenesis.
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