Role of RNA-Binding Proteins in BCR/ABL Leukemogenesis

描述（由申请人提供）：穿梭hnRNP在真核mRNA从转录活性位点到翻译活性位点的整个过程中控制其命运;因此，造血细胞中其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RNA结合蛋白的水平显著增加，包括FUS、hnRNP A1、hnRNP E2和hnRNP K，四种穿梭的hnRNP参与mRNA生物发生、加工、核输出和翻译的调节。FUS、hnRNP A1和hnRNP E2的异位表达和/或活性抑制影响正常和BCR/ABL表达细胞的增殖、存活和分化，表明某些RNA结合蛋白的表达/活性增强在BCR/ABL白血病发生中起重要但尚未认识到的作用。因此，本研究的目的是：1）研究hnRNP E2和hnRNP A1在BCR/ABL表达细胞中表达/功能的调控机制。2)鉴定CML急变期和慢性期细胞中hnRNP A1和hnRNP E2相关mRNA编码蛋白的差异表达。3)确定调节hnRNP K表达/功能的BCR/ABL依赖性机制，并确定hnRNP K功能是否是BCR/ABL诱导的白血病发生所必需的。

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.