Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, 10065, USA.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
Nat Commun. 2018 Jan 9;9(1):110. doi: 10.1038/s41467-017-02618-6.
Aberrant gene expression is a hallmark of acute leukemias. MYB-driven transcriptional coactivation with CREB-binding protein (CBP)/P300 is required for acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex and rapidly accumulates in the nuclei of AML cells. Treatment of AML cells with MYBMIM led to the dissociation of the MYB:CBP/P300 complex in cells, its displacement from oncogenic enhancers enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. AML cells underwent mitochondrial apoptosis in response to MYBMIM, which was partially rescued by ectopic expression of BCL2. MYBMIM impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings elucidate the dependence of human AML on aberrant transcriptional coactivation, and establish a pharmacologic approach for its therapeutic blockade.
基因表达异常是急性白血病的一个标志。MYB 驱动的转录共激活与 CREB 结合蛋白（CBP）/P300 对于急性淋巴细胞白血病和髓系白血病是必需的，包括难治性 MLL 重排白血病。我们使用结构导向的分子设计，开发了一种肽模拟抑制剂 MYBMIM，它可以干扰分子 MYB：CBP/P300 复合物的组装，并迅速积累在 AML 细胞的核内。用 MYBMIM 处理 AML 细胞导致细胞中 MYB：CBP/P300 复合物的解离，其从富含 MYB 结合位点的致癌增强子上的位移，以及 MYB 依赖性基因表达的下调，包括 MYC 和 BCL2 癌基因。AML 细胞对 MYBMIM 发生线粒体凋亡，BCL2 的异位表达部分挽救了这一过程。MYBMIM 抑制白血病的生长，并延长了免疫缺陷小鼠移植原发性患者来源的 MLL 重排白血病细胞的存活时间。这些发现阐明了人类 AML 对异常转录共激活的依赖性，并为其治疗阻断建立了一种药理学方法。
