DDX11突变通过激活P38MAPK/PI3K/Akt/CREB信号通路调控钙调蛋白结合蛋白促进成人AML复发的作用机制研究

成人急性髓系白血病（Acute Myeloid Leukemia, AML）具有极高的临床及分子生物学异质性，复发是制约其长期预后改善的关键因素之一。探索新的复发相关分子标记物并研究其临床意义及病理机制具有重要价值。DDX11（DEAD/H-Box Helicase 11）编码一种DNA解旋酶，在维持基因组稳定性方面发挥重要作用。我们前期研究首次发现初诊成人AML中存在DDX11突变且与不良预后相关，初步功能实验提示DDX11突变可能通过激活CREB等信号通路，调控钙调蛋白结合蛋白促进AML复发。本研究拟在前期研究基础上，设计前瞻性临床队列进一步确证DDX11突变与临床预后的关系；利用慢病毒转染技术扩建DDX11突变型AML细胞株并建立异种移植免疫缺陷鼠模型，体内外实验研究DDX11突变对AML细胞生物学行为的影响并进一步探索潜在的分子机制，为成人AML精准诊疗提供实验依据。

Acute myeloid leukemia (AML) is a group of disease with extremely high clinical and molecular biological heterogeneity. Recurrence is one of the pivotal factors restricting the improvement of the long-term prognosis of adult AML. It is of great significance to explore new molecular markers related to recurrence and study their clinical significance as well as pathological mechanisms. DDX11(DEAD/H-Box Helicase 11) encodes a DNA helicase that plays pivotal roles in maintaining genome stability. Our previous research found for the first time that DDX11 was frequently mutated in newly diagnosed adult AML, which was associated with poor prognosis. Preliminary functional studies suggest that DDX11 mutations may promote the recurrence of AML through regulating calmodulin binding protein by activating the CREB signaling pathway. Based on our previous research, we intend to further determine the prognostic value of DDX11 mutation in adult AML by detecting more samples in the prospective clinical cohort of our center. Furthermore, DDX11 mutant AML cell lines and primary cells as well as xenograft mouse models will be constructed to evaluate the effects of DDX11 mutations on the biological behavior of AML cells such as proliferation, apoptosis, drug sensitivity and genome stability in vitro and in vivo. The study is expected to find and validate a new prognostic-related molecular marker, which will provide experimental evidence for fine-stratified diagnosis, prognostic evaluation and targeted therapy for adult AML.