SHQ1促进急性T淋巴细胞白血病的机制和功能研究

急性T淋巴细胞性白血病（T-ALL）是儿童青少年人群中较为常见的恶性血液肿瘤，严重威胁未成年患者的生命健康，然而其病理机制尚不完全明了。申请人前期通过全基因组表达谱测序分析发现参与RNA修饰的基因SHQ1在人源T-ALL中异常高表达，而且基因表达受到关键癌蛋白的驱动；推测SHQ1在T-ALL的发生发展中发挥重要促癌作用，目前尚无相关报道。基于此, 本项目拟聚焦SHQ1，通过分子生物学、细胞生物学和模式动物等学科交叉的研究方法，(1) 探讨SHQ1在T-ALL发生发展过程中的功能重要性，(2)分析SHQ1在T-ALL中受到NOTCH1和TAL1双重转录调控的分子机制，(3) 阐明SHQ1通过调节c-MYC剪接效率促进T-ALL的作用机理。本项目的顺利实施将会揭示SHQ1介导T-ALL癌蛋白网络调控促进白血病发生发展的新机制，预期成果有望为针对SHQ1的白血病靶向治疗开启新思路。

Acute T-cell lymphoblastic leukemia (T-ALL) is a common aggressive and life-threatening hematological malignancy often occurring in children and adolescents, yet molecular pathogenesis of which remains unclear. We have performed a genome-wide gene expression profiling revealing that aberrant expression of SHQ1, a factor involved in RNA modification, in primary T-ALL samples. The high expression of SHQ1 seems driven by major oncogenic transcriptional factors in T-ALL, suggesting a potential pivotal role of SHQ1 in T cell leukemogenesis. For this, we aim to understand whether and how SHQ1 functions to put forward T-ALL. Using combinatory approaches of molecular biology, cellular biology and animal modeling, we will (1) examine how SHQ1 loss affects T-ALL cell proliferation and survival in vitro and evaluate the functional role of SHQ1 in bone marrow transplant and patient-derived xenograft T-ALL models; (2) study the mechanism how SHQ1 transcription was activated by major oncogenes NOTCH1 and TAL1; (3) decipher the molecular mechanism whereby SHQ1 affects T-ALL cell proliferation through regulating c-MYC mRNA splicing. Our work will identify a novel T-ALL promoting factor and decipher a previously unsuspected mechanism involved in T-ALL pathogenesis. Ultimately, it raises a possibility and paves a new avenue of translating anti-SHQ1 therapy in T-ALL treatments.