BRCA1介导HDACI协同化疗药物杀伤AML细胞的机理研究

Acute myeloid leukemia (AML) remains a challenging disease to treat in both pediatric and adult populations. Resistance to anthracycline [e.g., daunorubicin (DNR)] and cytarabine (ara-C)-based chemotherapy is a major cause of treatment failure in this disease. Histone deacetylase (HDAC) inhibitors (HDACIs) are a promising new class of anti-cancer drugs, which induce differentiation, cell cycle arrest, and apoptosis in human leukemic cells,but less so in normal cells. Our previous studies demonstrated synergistic antileukemic cytotoxicities between HDACIs and ara-C in AML cell lines and diagnostic AML blasts. This was accompanied by cooperative induction of DNA double-strand breaks (DSBs) and apoptosis.However, the underlying molecular mechanisms remain largely unknown. Further, HDAC family members that are involved in the synergistic anti-leukemic activities with combined ara-C and HDACIs were not identified.As a logical extension of our previous studies, we will continue to explore the molecular mechanisms by which HDACIs enhance DNA damaging agent-induced DNA DSBs and apoptosis. The ability of HDACIs to enhance ara-C-induced DNA DSBs and apoptosis suggests that they may suppress the DNA damage response (DDR) in AML cells. The DDR represents a complex network of multiple signaling pathways involving cell cycle checkpoints, DNA repair, transcriptional programs, and apoptosis. In cancer treatment, the DDR occurs in response to DNA damaging agents (e.g., ara-C and DNR), representing an important mechanism limiting chemotherapeutic efficacy. We hypothesize that HDACIs enhance ara-C- or DNR-induced apoptosis in AML cells by suppressing the DDR. This hypothesis is strongly supported by our preliminary studies.We found that HDACIs suppresse the expression of BRCA1, a critical gene in the DDR, in AML cell lines and primary AML patient samples.Our proposed studies will identify the HDACs which regulate the expression of BRCA1 in AML cells and determine the molecular mechanisms by which these HDACs regulate the expression of BRCA1. These results will be critical in designing the next generation HDACIs that show the best efficacies in treating AML with potentially reduced toxicity. Most importantly, our studies will establish a more efficacious therapy that combines HDACIs and standard chemotherapy drugs for treating AML and potentially other cancers.

急性髓细胞白血病（AML）是一种常见的恶性血癌，许多患者死于耐药、复发或并发症。最近的研究表明，组蛋白去乙酰化酶抑制剂类药物（HDACI）能促进AML细胞分化和凋亡。我们发现HDAC抑制剂类药物可通过抑制DNA修复基因BRCA1的表达，阻碍DNA修复，并由此增强化疗药物引起的DNA双链断裂，促进凋亡产生。并且发现，与BRCA1的表达直接相关的主要是HDAC1，2，3中的一种或几种。因此，本研究拟研究BRCA1对化疗药物引起的DNA损伤和细胞凋亡的影响，然后寻找与BRCA1表达相关的HDAC，最后研究HDAC抑制剂抑制BRCA1表达的机理。这将为HDAC抑制剂类药物在AML治疗中与常规化疗药物的联合应用提供明确的分子机制，为今后设计特异性更高的HDACI提供依据。随着相关机理的研究，本研究不但会为BRCA1成为常规化疗药物联合用药的新靶点提供重要的依据，还可为今后开发BRCA1抑制剂提供参考

急性髓细胞白血病（AML）是一种常见的恶性血癌，许多患者死于耐药、复发或并发症。最近的研究表明，组蛋白去乙酰化酶抑制剂类药物（HDACI）能促进AML细胞分化和凋亡。我们发现HDAC抑制剂类药物可通过调控DNA修复基因BRCA1的转录，抑制DNA修复，并由此增强化疗药物引起的DNA双链断裂，促进凋亡产生。并且发现，与BRCA1的表达直接相关的主要是HDAC1，2，3中的一种或几种。因此，本研究拟研究BRCA1对化疗药物引起的DNA损伤和细胞凋亡的影响，然后寻找与BRCA1表达相关的HDAC，最后研究HDAC抑制剂抑制BRCA1表达的机理。这将为HDAC抑制剂类药物在AML治疗中与常规化疗药物的联合应用提供明确的分子机制，为今后设计特异性更高的HDAC提供依据。随着相关机理的研究，不但会为BRCA1成为常规化疗药物联合用药的新靶点提供重要的依据，还可为今后开发BRCA1抑制剂提供参考。