FLT3/ITD突变-HIF1α-DNA甲基化环路诱导AML复发耐药的新机制

伴FLT3/ITD基因突变的急性髓细胞白血病（AML）患者易耐药复发，预后差，临床尚无有效治疗手段。阐明耐药复发机制、开展分子靶向治疗，对提高疗效、改善患者预后有重要意义。我们最近报道了缺氧诱导因子（HIF）1α诱导DNA甲基化促进白血病发生的新机制，但其与FLT3/ITD AML耐药和复发的关系尚不清楚。我们前期实验发现，沉默FLT3/ITD能抑制HIF1α表达、DNA甲基化及白血病细胞增殖，因此设想FLT3/ITD通过活化HIF1α诱导DNA甲基化，使调控FLT3、HIF1α的抑癌基因被沉默，促进AML耐药复发。本项目拟阐明FLT3/ITD、HIF1α、DNA甲基化三者间的调控环路，观察异常甲基化模式与FLT3/ITD AML复发的关系，验证联合靶向抑制FLT3和HIF1α对耐药白血病的疗效。研究结果有助于从遗传学/表观遗传学交互作用的新视角认识白血病复发耐药机制、开发靶向治疗新策略。

Acute myeloid leukemia (AML) patients with FLT3/ITD mutation tend to have a higher risk of drug resistance and relapse, and have a poor prognosis. Effective treatments are still not available in current clinical practice. Clarify the mechanisms of drug resistance and relapse and develop molecular targeted therapies will contribute to improve the efficacy of treatment and the prognosis of patients. We have recently reported a new mechanism that hypoxia inducible factor (HIF) 1α promotes leukemogenesis through inducing DNA methylation. However, its relationship to the drug resistance and relapse in FLT3/ITD AML remains unclear. We conducted preliminary experiments and found that the silence of FLT3/ITD gene expression led to inhibition of HIF1α level, DNA methylation, and leukemia cell proliferation. We therefore hypothesize that DNA methylation through FLT3/ITD-mediated HIF1α activation leads to gene expression silence of tumor suppressors targeting FLT3 and HIF1α, and thereby induces drug resistance and relapse in AML. The present study is designed to demonstrate the regulatory circuit among FLT3/ITD, HIF1αand DNA methylation, investigate the correlation between the aberrant methylation pattern and relapse of FLT3/ITD AML, and test the therapeutic effect of combined targeting inhibition of FLT3/ITD and HIF1αon drug resistance in leukemia. The results will provide mechanistic insights to leukemia relapse and drug resistance from a new angle of genetic/epigenetic interaction and important guide for new targeting therapeutic strategies.