TRANSCRIPTION FACTOR REGULATION BY THE BCR/ABL ONCOGENE

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Transcription factor regulation by the BCR/ABL oncogene Human hematological malignancies are characterized by well- defined genetic abnormalities responsible for the generation of autonomous growth signals or the aberrant transduction of these signals from the cytoplasm to the nucleus. 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. The mechanisms of activation of the cytoplasmic downstream effectors of BCR/ABL are understood in some detail, but much less is known on the pathways leading to transcription factor regulation. This application focuses on investigating the BCR/ABL-dependent pathways leading to changes in the expression of c-Myb and C/EBPalpha, two transcription factors involved in the regulation of proliferation, survival, and differentiation of hematopoietic cells. Specifically, we will: 1) Investigate mechanisms of the enhanced expression/activity of c-Myb by: a. determining sequence requirements and enzymatic pathways that regulate ubiquitination and/or proteasome-dependent degradation of c-Myb in normal and BCR/ABL-expressing hematopoietic cells. b. identifying the interacting proteins promoting the ubiquitin/proteasome-dependent degradation of c-Myb. c. determining whether the activity of proteins promoting c-Myb degradation is modulated in BCR/ABL-expressing cells. 2) Assessing the effects of degradation-resistant c-Myb mutants on proliferation, survival, and differentiation of hematopoietic cells. 3) Assessing leukemic samples for the presence of c-myb mutations within domains involved in protein degradation. 4) Investigating the mechanisms whereby BCR/ABL suppresses the expression of the granulocytic differentiation regulator C/EBPalpha.