Gopalakrishnapillai Anilkumar, Kolb E Anders, McCahan Suzanne M, Barwe Sonali P
Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
Nemours Bioinformatics Core Facility, Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
Leuk Res. 2017 Jul;58:91-97. doi: 10.1016/j.leukres.2017.05.004. Epub 2017 May 5.
Aberrations in epigenetic modifications contribute to leukemogenesis in childhood acute myeloid leukemia (AML). We combined DNA hypomethylating agent azacitidine with histone deacetylase inhibitor panobinostat in preclinical models of childhood AML. Synergistic cytotoxic effect upon treatment with azacitidine and panobinostat with combination indices <1.0 was observed. Azacitidine and panobinostat increased median survival by 26 and 6days respectively in MV4;11 xenografted mice. Mice treated with both drugs showed a drastic reduction in leukemic burden leading to complete remission sustained for the duration of the experimental period lasting more than 519days. Reduced leukemic burden and prolonged survival was also observed in AML-193 xenografted mice treated with azacitidine-panobinostat combination. Differential gene expression profiling was performed on AML cells treated with azacitidine, panobinostat or azacitidine-panobinostat combination. Functional mapping of transcripts uniquely regulated by the azacitidine-panobinostat combination in MV4;11 cells identified p53 as an upstream regulator. A comparison of the uniquely modulated transcripts by azacitidine-panobinostat combination in MV4;11 cells versus AML-193 and THP-1 cells, bearing mutated p53, also revealed p53 as the topmost upstream regulator. Finally, expression of mutant p53 in MV4;11 cells reduced sensitivity to azacitidine-panobinostat combination, suggesting that p53 may be a predictor of response to epigenetic therapy in pediatric AML.
表观遗传修饰异常在儿童急性髓系白血病（AML）的白血病发生过程中起作用。我们在儿童AML的临床前模型中将DNA低甲基化剂阿扎胞苷与组蛋白脱乙酰酶抑制剂帕比司他联合使用。观察到阿扎胞苷和帕比司他联合治疗具有协同细胞毒性作用，联合指数<1.0。在MV4;11异种移植小鼠中，阿扎胞苷和帕比司他分别使中位生存期延长了26天和6天。两种药物联合治疗的小鼠白血病负担显著降低，导致完全缓解，并在超过519天的实验期内持续缓解。在接受阿扎胞苷 - 帕比司他联合治疗的AML - 193异种移植小鼠中也观察到白血病负担减轻和生存期延长。对用阿扎胞苷、帕比司他或阿扎胞苷 - 帕比司他联合治疗的AML细胞进行了差异基因表达谱分析。对MV4;11细胞中由阿扎胞苷 - 帕比司他联合独特调节的转录本进行功能定位，确定p53为上游调节因子。比较MV4;11细胞中阿扎胞苷 - 帕比司他联合独特调节的转录本与携带突变p53的AML - 193和THP - 1细胞，也显示p53是最主要的上游调节因子。最后，MV4;11细胞中突变p53的表达降低了对阿扎胞苷 - 帕比司他联合治疗的敏感性，表明p53可能是儿童AML对表观遗传治疗反应的预测指标。
