HSP27通过自噬调控急性髓系白血病M4/M5多药耐药的分子机制研究

探讨多药耐药（MDR）分子机制 、提高患者存活率，仍然是白血病研究的热点。项目组在《leukemia》上报道了自噬是白血病MDR产生的新机制。近期，项目组在《Oncol Rep》上首次报道了热休克蛋白27（HSP27）参与了儿童AML-M4/M5的发病，是白血病的重要致病基因。同时，我们发现抑制HSP27表达减少了化疗药物诱导的自噬，并增加了化疗药物的敏感性。本项目在上述研究基础上，提出HSP27调控AML-M4/M5白血病自噬，进而影响白血病MDR产生的假说。针对上述假说，本项目拟采用基因转染、RNA干扰、免疫共沉淀、Western blot、电镜分析、流式细胞术等先进研究手段，进一步深入系统的探讨HSP27通过自噬调控AML-M4/M5白血病细胞MDR产生的分子机制。开展本项目可望揭示HSP27在AML-M4/M5的作用机制，为寻找儿童AML-M4/M5靶向治疗及克服MDR提供新思路。

Multidrug resistance(MDR) is a major obstacle to the successful treatment of leukemia. Exploring the molecular mechanism of MDR is still the tpoic in cancer research.Acute myeloid leukemia(AML) represents 20% of all acute leukemia(AL) cases in children and adolescents. Clinical outcome of patients with AML remains poor with a long-term survival of 30-50% in pediatric patients.In childhood AML, MLL gene rearrangements at chromosome band 11q23 are mainly restricted to the FAB M4 and M5 subtypes, which confer a poor prognosis. The identification of prognostic factors and aberrant signaling pathways in AML-M4/M5 is important for the development of new molecular therapies and might improve risk-adapted therapeutic strategies for AML patients. Our recent study demonstrated that autophagy is a crucial regulator of leukemia MDR. Recently,we found that heat shock protein 27（HSP27）was expressed abundantly in pediatric newly diagnosed/relapsed AML-M4/M5 patients and M4/M5 cell lines, which maybe a important oncogene of leukemia. Meanwhile,inhibition of HSP27 expression in THP-1 cells reduced anti-cancer drugs-induced autophagy and increased the sensitivity of leukemia cells to chemotherapentic drugs. Based on these findings, our hypothesis is that HSP27 regualtes AML-M4/M5 MDR by autophagy. We will futherly determine whether HSP27 regulated autophagy in leukemia and the signal pathways of HSP27-mediated autophagy for AML-M4/M5 chemoresistance.In light of the therapeutic promise of autophagy inhibitors to render tumor cells more susceptible to conventional therapies, our discovery that HSP27 is an important regulator of autophagy in AML-M4/M5 cells may lead to the development of novel strategies for the treatment of human leukemia.