剪切因子SRSF1异型体2在儿童急性淋巴细胞白血病中作用机制的研究

白血病是儿童最常见的恶性肿瘤和死亡原因，但发病机理尚不清楚。剪接因子SRSF1是第一个被证明与肿瘤相关的原癌蛋白。我们前期研究表明SRSF1在儿童急性淋巴细胞白血病（ALL）中异常表达，并发现SRSF1在白血病细胞中具有两种异型体，异型体2（IS2）具有肿瘤抑制作用，且在生理状态下IS2通过3’端非翻译区可变剪切可向异型体1（IS1）转换，IS1/IS2比例增高与白血病预后差相关。课题假说：SRSF1蛋白IS2向IS1转换引起细胞生物学功能变化，促进儿童ALL的发生。本课题将：（1）研究SRSF1-IS2对白血病细胞增殖、凋亡、克隆形成能力等生物学特性的影响；（2）筛选参与调控IS2向IS1转换的RNA结合蛋白及蛋白激酶，探索其转化机制；（3）建立稳定表达各异型体白血病细胞系，构建相应白血病小鼠模型，应用KD-激酶腺病毒/激酶小分子抑制剂进行干预，探索白血病治疗新靶点。

Leukemia is the most frequent malignant neoplasm and the major cause of death in children, but the pathogenesis of the disease remains unclear. The serine/arginine-rich splicing factor 1 (SRSF1) was the first proto-oncoprotein recognized to be associated with tumors. Our previous research has showed that SRSF1 expressed aberrantly in pediatric acute lymphoblastic leukemia (ALL) and SRSF1 was expressed as two distinct isoforms. We first discovered isoform2 might play a tumor-suppressor role and a novel alternative splicing manner happened at 3’-untranslated region (UTR) of physiological isoform2 which led to physiological isoform2 switched to isoform1. And increased ratio of isoform1/isoform2 was correlated with poor prognosis of ALL. The hypothesis is that the conversion of SRSF1 protein isoform2 to isoform1 causes changes in cell biological function, which promotes the occurrence of ALL in children. In this research we will (1) study the effect of SRSF1-isoform2 on the proliferation, apoptosis and colony formations of leukemia cells; (2) explore the switch mechanism of isoform2 to isoform1 by selecting RNA binding proteins and kinases involved in the regulation process; (3) generate isoform specific stable leukemic cell lines and corresponding mouse models to explore new therapeutic targets for treating leukemia by applying kinase dead (KD)-kinase adenovirus or kinase small-molecule inhibitors.