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.
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.
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