Transcription Factor Regulation by the BCR/ABL Oncogene

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DESCRIPTION (provided by applicant): The BCR/ABL oncoproteins, the leukemia-specific gene products of the Philadelphia chromosome (Ph1) translocation, induce and maintain the leukemic phenotype through their deregulated tyrosine kinase activity; such activity is essential for recruitment and activation of multiple pathways that transduce signals leading to growth factor-independent proliferation, inhibition of apoptosis, and altered differentiation of myeloid precursor cells. While the mechanisms of activation of the cytoplasmic downstream effectors of BCR/ABL are understood in some detail, much less is known on the pathways leading to transcription factor regulation. In this application we will investigate the BCR/ABL-dependent pathways leading to changes in the expression of the transcription factor c-Myb and assess the role of c-Myb and c-Myb targets in the regulation of proliferation, survival, and differentiation of BCR/ABL-expressing hematopoietic progenitors by: 1) Investigating the role of the F-box protein FBXL-3 in regulating c-Myb levels in p210 BCR/ABL-expressing cells by assessing: a) the mechanisms of FBXL-3-dependent degradation of c-Myb; b) the effects of FBXL-3 in normal and p210BCR/ABL-expressing hematopoietic progenitors. 2) Investigating the requirement of c-Myb in p210BCR/ABL-dependent leukemogenesis by assessing: a) role and requirement of the c-Myb target c-Kit in transformation and leukemogenesis of p210BCR/ABL-expressing c-Myb and c-Myb primitive hematopoietic progenitors; b) cooperation of c-Myb targets c-Kit and Bcl-2 in transformation and leukemogenesis of p210BCR/ABL -expressing c-Myb primitive hematopoietic progenitors. c) effects of the c-Myb target Jak2 , individually and in cooperation with c-Kit, in transformation and leukemogenesis of p210BCR/ABL-expressing hematopoietic progenitors. 3) Investigate the requirement of c-Myb in p190BCR/ABL-dependent leukemogenesis by assessing: a) transformation and leukemogenesis of B-cell progenitor subsets from double transgenic p190BCR/ABL/c-Myb mice; b) leukemogenesis of c-Myb-silenced p190BCR/ABL-expressing Z-181 human B-cell leukemia cells in NOD-SCID mice; c) the role of c-Myb targets identified by microarray hybridization in p190BCR/ABL-dependent leukemogenesis. PUBLIC HEALTH RELEVANCE: Leukemias are malignancies of blood cell progenitors which may be caused by specific chromosomal abnormalities. In chronic myelogenous leukemia and in acute leukemias associated with the Philadelphia chromosome, the BCR/ABL oncogene promotes transformation of hematopoietic cells by activating nuclear proteins such as c-Myb. Understanding the role of c-Myb in leukemogenesis is important for developing therapies based on inhibition of its expression/activity.