Role of BAZ2A in MLL-r leukemia and therapeutic response

项目总结/摘要 MLL重排（MLL-r）白血病占人类急性白血病的5-10%，并且与 预后不良。未满足的临床需求和缺乏有效的MLL-r靶向治疗 白血病强调需要新的治疗方案。最近的癌症表观遗传学研究发现， 组蛋白H3赖氨酸79（H3 K79）甲基转移酶DOT 1 L在MLL-r白血病发生中的中心作用。 已经注意到DOT 1 L抑制剂作为单一药剂治疗的重要临床应答，然而， 预计联合治疗是必要的。 我们基于MLL-r白血病中DOT 1 L抑制剂致敏筛选的初步研究已经确定 BAZ 2A的抑制显著增加DOT 1 L抑制剂的抗白血病活性。客观 本申请的目的是确定介导SIRT 1可用性的关键表观遗传机制， 抑制MLL-r白血病癌基因表达。我们的中心假设是BAZ 2A，一种染色质， 重塑蛋白的rDNA基因座，介导SIRT 1的重新分配，组蛋白去乙酰化和沉默， MLL-r/DOT 1 L驱动的癌基因。我们将剖析BAZ 2A/SIRT 1染色质靶向机制（目的1）， 研究DOT 1 L和BAZ 2A联合治疗的疗效（目标2），并验证一种新的饱和度 CRISPR蛋白质扫描技术用于DOT 1 L和BAZ 2A中功能元件的从头发现 (Aim 3）。 这项研究是创新的，因为（1）它引入了同时靶向多个 组成部分的表观遗传网络，以有效地抑制癌症程序，（2）它建立了一个 全新的基因筛选方法，用于亚蛋白水平的功能结构域发现。这样做的影响 研究将具有重要意义，因为（1）它立即提供了新的治疗机会 针对难以治疗的MLL-r白血病，和（2）它将有助于确定新的功能元件， 表观遗传调节剂用于未来的药物靶向。

PROJECT SUMMARY/ABSTRACT MLL-rearranged (MLL-r) leukemias account for 5-10% of human acute leukemia and is associated with poor prognosis. The unmet clinical needs and the lack of an effective targeted therapy to the MLL-r leukemias emphasize the need for novel regimens. Recent cancer epigenetics studies discovered a central role for the histone H3 lysine 79 (H3K79) methyltransferase DOT1L in MLL-r leukemogenesis. Important clinical responses have been noted with DOT1L inhibitor treatment as a single agent, however, it is expected that combination treatments will be necessary. Our preliminary studies based on a DOT1L-inhibitor sensitization screen in MLL-r leukemia have identified suppression of BAZ2A significantly increases the anti-leukemic activity of the DOT1L inhibitor. The objective of this application is to determine the critical epigenetic mechanisms that mediate the availability of SIRT1 to suppress oncogene expression in MLL-r leukemia. Our central hypothesis is that BAZ2A, a chromatin remodeling protein of rDNA loci, mediates redistribution of SIRT1 for histone deacetylation and silencing of MLL-r/DOT1L-driven oncogene. We will dissect the BAZ2A/SIRT1 chromatin targeting mechanisms (Aim 1), investigate the efficacy of DOT1L and BAZ2A combination therapies (Aim 2), and validate a novel saturation CRISPR protein scan technology for de novo discovery of the functional elements in DOT1L and BAZ2A (Aim 3). This study is innovative because (1) it introduces a novel concept of simultaneously targeting multiple components of an epigenetic network to efficiently suppress the cancer programs, and (2) it establishes a brand new genetic screen approach for a sub-protein level functional domain discovery. The impact of this research will be of significance because (1) it immediately provides novel therapeutic opportunities against the difficult-to-treat MLL-r leukemias, and (2) it will help identify novel functional elements in epigenetic regulators for future pharmaceutical targeting.