Transcription Factor Regulation by the BCR/ABL Oncogene

描述(申请人提供)：bcr/abl癌蛋白，白血病特异的基因产物的费城染色体(PH1)易位，诱导和维持白血病表型通过其解除调节的酪氨酸激酶活性；这种活性是必不可少的招募和激活的多个途径，转导信号导致生长因子非依赖性的增殖，抑制凋亡，并改变分化的髓系前体细胞。虽然对bcr/abl胞质下游效应器的激活机制有了较详细的了解，但对导致转录因子调控的途径知之甚少。在这项应用中，我们将研究bcr/abl依赖的途径导致转录因子c-Myb的表达变化，并通过以下方式评估c-Myb和c-Myb靶点在调控bcr/abl表达的造血祖细胞增殖、存活和分化中的作用：1)通过评估以下方面来研究F-box蛋白FBXL-3在调节p210bcr/abl表达的细胞中的c-Myb水平的作用：a)依赖FBXL-3的c-Myb降解机制；b)FBXL-3在正常和p210BCR/ABL表达的造血祖细胞中的作用。2)探讨c-Myb在p210BCR/ABL依赖的白血病发生中的作用：a)c-Myb靶标c-Kit在表达p210BCR/ABL的c-Myb和c-Myb原始造血祖细胞转化和白血病发生中的作用和要求；b)c-Myb靶标c-Kit和Bcl2在p210BCR/ABL表达的c-Myb原始造血祖转化和白血病发生中的协同作用。C)c-Myb靶向JAK2单独或与c-Kit协同在p210BCR/ABL表达的造血祖细胞转化和白血病发生中的作用。3)研究c-Myb在p190BCR/ABL/c-Myb双转基因小鼠B细胞亚群转化和白血病发生中的作用；c)c-Myb沉默的p190BCR/ABL表达的人B细胞白血病细胞在NOD-SCID小鼠中的白血病发生；c)基因芯片杂交鉴定的c-Myb靶点在p190BCR/ABL依赖的白血病发生中的作用。

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.