Targeting MLL/Menin in AML

摘要： 高达40%的急性白血病患者存在同源异型(HOX)基因等基因的不适当表达 髓系白血病(AML)。两个众所周知的基因亚集，那些具有MLL重排的和那些 与NPM1突变，已知具有HOX基因的高水平表达，并已被证明是 依赖于这些基因的持续表达。最近的研究定义了蛋白质复合体 维持这种异常的基因表达。此外，多家集团和制药/生物技术公司现在已经 开发了这些络合物的小分子抑制剂。其中一些小分子，特别是那些 靶向DOT1L、EZH2和溴域)最近进入早期试验，并显示出兴趣 生物学和一些完全的临床反应。靶向染色质相关复合体的另一种方法 是抑制MLL1-Menin相互作用，这也是一种逆转Hox基因的方法 表情。在这项提案中，我们将对新开发的MLL1-Menin抑制剂进行表征，并努力推出一种 对这些小分子进行临床评估。在特定的目标1中，我们将描述对基因的影响 MLL重排和NPM1抑制MLL1-Menin相互作用后的表达和染色质状态 突变的AML细胞。在特定目标2中，我们将评估MLL1-Menin抑制剂与以下两种药物的组合 氮胞苷、DOT1L抑制剂或Flt3抑制剂。在特定目标3中，我们将启动MLL-1 Menin的第一阶段试验 单独使用和与氮胞苷联合使用的抑制剂。这些试验将为进一步 根据这里描述的临床前研究结果对联合治疗进行评估。建议数 实验将推动MLL1-Menin抑制剂进入临床评估，并重要地确定组合 应该在未来的临床研究中评估的方法。

Abstract: Inappropriate expression of genes such as the homeotic (HOX) genes is found in up to 40% of cases of Acute Myelogenous Leukemia (AML). Two well-known genetic subsets, those with MLL-rearrangements and those with NPM1 mutations, are known to possess high-level expression of HOX genes and have been shown to be dependent on continued expression of these genes. Recent studies have defined the protein complexes that maintain this aberrant gene expression. Furthermore, multiple groups and pharma/biotech companies have now developed small molecule inhibitors of these complexes. Some of these small molecules, particularly those targeting DOT1L, EZH2 and Bromodomains) have recently entered early phase trials and have shown interesting biological and some complete clinical responses. Another approach to target chromatin associated complexes is inhibition of the MLL1-Menin interaction, an approach that has also been shown to reverse HOX gene expression. In this proposal we will characterize newly developed MLL1-Menin inhibitors and work to bring one of these small molecules to clinical assessment. In Specific Aim 1 we will characterize the effects on gene expression and chromatin state after inhibition of the MLL1-Menin interaction in MLL-rearranged and NPM1 mutant AML cells. In Specific Aim 2 we will assess the combination of MLL1-Menin inhibitors with either azacitidine, DOT1L inhibitors or FLT3 inhibitors. In Specific Aim 3 we will initiate a phase 1 trial of MLL-1 Menin inhibitors alone and in combination with a azacitidine. These trials that will set the foundation for further assessment of combinations based on results from preclinical studies described here. The proposed experiments will propel MLL1-Menin inhibitors to clinical assessment and importantly define combination approaches that should be assessed in future clinical studies.