MLL型AML恶性程度高且预后差，常规化疗药难以奏效，因此探寻新型有效的临床治疗策略意义重大。已有临床前研究报道PARP抑制剂对DNA同源重组修复缺陷型AML疗效显著，但对同源重组修复正常的MLL型AML不敏感。申请人前期发现：PI3K催化亚基p110γ抑制剂IPI549显著增强MLL型AML细胞对PARP抑制剂BMN673治疗的敏感性，诱导细胞分化，增加凋亡；进一步研究发现：抑制p110γ导致同源重组修复相关基因表达下调。由此推测：抑制p110γ引起MLL型AML细胞DNA损伤同源重组修复缺陷，与PARP抑制剂联用可协同杀伤MLL型AML。为证明此假说，本项目拟用AML细胞系、临床标本及PDX模型结合转录组学分析，深入探寻PI3K p110γ抑制剂联合PARP抑制剂BMN673产生合成致死效应的分子机制并加以验证，为建立基于PARP抑制剂治疗MLL型AML的联合靶向治疗方案提供新思路。

MLL-rearranged AML is highly malignant and associated with poor prognosis, remaining a major obstacle to successful chemotherapies. Therefore it is of great significance to explore new and effective clinical treatment strategies. A number of studies have reported that PARP inhibitors can effectively treat homologous recombination repair (HRR) deficient AML. However, leukemia driven by mixed-lineage leukemia (MLL, encoded by KMT2A) fusions is largely proficient in HRR and thus insensitive to PARP inhibition. Our preliminary data revealed that PI3K p110γ inhibitor IPI549 significantly enhances the anti-tumor effect of PARP inhibitors in MLL-AML THP-1 cells, and induces cell differentiation and apoptosis. Further investigations indicated that inhibition of p110γ could down-regulate the expression of genes involved in homologous recombination. Built upon these findings, we hypothesized that pharmacological inhibition of p110γ results in deficient homologous recombination repair, enhancing the anti-tumor effect of PARP inhibitors in MLL-arranged AML. Herein, using AML cell lines, patient-derived primary AML cell culture and patient-derived tumor xenograft models, we propose to explore the underlying mechanism that accounts for the synergism between p110γ inhibitor and PARP inhibitor BMN673 in the synthetic lethality for MLL-AML treatment. The current project aims to provide insights into effective treatment of AML.