Role of RNA-Binding Proteins in BCR/ABL Leukemogenesis

描述(由申请人提供)：穿梭的hnRNPs控制着真核细胞mRNAs从转录活性部位到翻译活性部位的整个旅程；因此，它们在造血细胞中功能的获得或丧失可能导致造血改变和/或白血病的出现。在表达bcr/abl的细胞中，不同的RNA结合蛋白水平显著增加，包括FUS、hnRNP A1、hnRNP E2和hnRNP K，这四个穿梭的hnRNP参与调节mRNA的生物发生、加工、核输出和翻译。异位表达和/或抑制FUS、hnRNP A1和hnRNP E2的活性影响正常和bcr/abl表达细胞的增殖、存活和分化，提示某些RNA结合蛋白的表达/活性增强在bcr/abl白血病的发生中起着重要但尚未被认识的作用。因此，本建议的目的是：1)研究BCR/ABL表达细胞中hnRNP E2和hnRNP A1表达/功能的调控机制。2)鉴定在CML急变期和慢性期细胞中差异表达蛋白的hnRNP A1和hnRNP E2相关mRNAs。3)明确bcr/abl依赖的调节hnRNP K表达/功能的机制，并确定hnRNP K功能(S)是否参与bcr/abl诱导的白血病的发生。

DESCRIPTION (provided by applicant): Shuttling hnRNPs control the fate of eukaryotic mRNAs throughout their journey from the active site of transcription to that of translation; thus, gain or loss of their function in hematopoietic cells might result in altered hematopoiesis and/or emergence of leukemia. In BCR/ABL-expressing cells, there is a marked increase in the levels of different RNA binding proteins including FUS, hnRNP A1, hnRNP E2 and hnRNP K, four shuttling hnRNPs involved in the regulation of mRNA biogenesis, processing, nuclear export, and translation. Ectopic expression and/or inhibition of the activity of FUS, hnRNP A1 and hnRNP E2 affects the proliferation, survival, and differentiation of normal and BCR/ABL-expressing cells, suggesting that enhanced expression/activity of certain RNA-binding proteins plays an important but as yet unrecognized role in BCR/ABL leukemogenesis. Thus, the objective of this proposal is: 1) To investigate the mechanisms regulating hnRNP E2 and hnRNP A1 expression/function in BCR/ABL-expressing cells. 2) To identify hnRNP A1 and hnRNP E2-associated mRNAs encoding proteins differentially expressed in CML-blast crisis and CML-chronic phase cells. 3) To determine the BCR/ABL-dependent mechanisms regulating the expression/function of hnRNP K and determine whether hnRNP K function(s) is(are) required for BCR/ABL-induced leukemogenesis.