Role of BAZ2A in MLL-r leukemia and therapeutic response

项目摘要/摘要 MLL重排(MLL-r)白血病占人类急性白血病的5%-10%，与 预后不良。临床需求未得到满足，缺乏有效的靶向治疗 白血病强调了新疗法的必要性。最近的癌症表观遗传学研究发现 组蛋白H3赖氨酸79(H3K79)甲基转移酶DOT1L在MLL-r白血病发生中的中心作用。 已经注意到将DOT1L抑制剂作为单一药物治疗的重要临床反应，然而， 预计联合治疗将是必要的。 我们基于DOT1L抑制剂增敏筛查的MLL-r白血病的初步研究已经确认 抑制BAZ2A显著增加DOT1L抑制剂的抗白血病活性。目标是 这一应用的目的是确定介导SIRT1可用于 抑制MLL-r白血病的癌基因表达。我们的中心假设是BAZ2A，一种染色质 RDNA基因座重塑蛋白介导组蛋白去乙酰化和沉默SIRT1的重新分布 MLL-r/DOT1L驱动的癌基因。我们将剖析BAZ2A/SIRT1染色质靶向机制(目标1)， 研究DOT1L和BAZ2A联合疗法的疗效(目标2)，并验证一种新的饱和度 CRISPR蛋白质扫描技术用于DOT1L和BAZ2A功能元件的新发现 (目标3)。 本研究的创新之处在于：(1)引入了同时瞄准多个目标的新概念 表观遗传网络的组成部分，以有效地抑制癌症计划，以及(2)它建立了一种 全新的基因筛选方法，用于亚蛋白质水平的功能域发现。这件事的影响 研究将具有重要意义，因为(1)它立即提供了新的治疗机会 针对难治性的MLL-r白血病，以及(2)它将有助于识别新的功能元件 表观遗传调节器，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.