REV7通过跨损伤合成促进ALL耐药复发的作用机制研究

急性淋巴细胞白血病（ALL）是儿童最常见的恶性肿瘤，耐药复发是其治疗失败引起死亡的主要原因，也是研究的瓶颈。我们通过对儿童ALL初发复发配对样本的全基因组学研究，发现ALL复发过程中产生新的突变印迹A和B，两者均有C>G的突变特征，但未阐明其具体机制。申请者前期研究发现了跨损伤合成修复基因REV7具有促进C到G突变并促进B细胞存活的新功能，推测REV7的新功能与白血病耐药复发相关。我们进一步研究发现REV7不仅促进ALL细胞耐药存活，还发现REV7促进ALL细胞耐药突变。本项目研究REV7在化疗药物诱导产生基因突变及促进耐药细胞存活中的作用机制，进一步阐明其驱动儿童ALL耐药复发的机制，为优化儿童ALL的临床治疗方案和克服其耐药提供新的思路和策略，对新药研发提供重要理论。

Children acute lymphoblastic leukemia (ALL) is the most common malignant tumor in children, and drug resistance and tumor relapse is the main cause of death caused by the failure of its treatment, and it is also the bottleneck of research. Through a genomics research on paired samples of initial and relapse children ALL, we found that new mutation signatures A and B were generated during the recurrence of ALL, both of which had the mutation characteristics of C>G, but the specific mechanism was not clarified. The applicant previous study found that the translesion synthesis repair gene REV7 has a new function of promoting C to G mutations and promoting the survival of B cells. It is speculated that the new function of REV7 is related to the relapsed ALL. Our further study found that REV7 not only promotes the survival of ALL cells with resistance, but also found that REV7 promotes resistance mutations in ALL cells. This project investigates the mechanism of REV7 in the induction of gene mutations by chemotherapy and the promotion of drug-resistant cell survival, and further clarifies the mechanism that drives the recurrence of resistance in children with ALL, in order to provides new ideas and strategies to optimize the clinical treatment of children with ALL and overcome its drug resistance, and provides important theories for the development of new drugs.