Defining epigenetic mechanisms in NPM1c mutant leukemia

定义 NPM1c 突变白血病的表观遗传机制

• 批准号: 10184546
• 负责人: SCOTT A ARMSTRONG
• 金额: $ 40.36万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-09 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10184546
• 关键词: Acute Myelocytic Leukemia; Adaptor Signaling Protein; Architecture; Binding; Bioavailable; Cell Survival; Cells; Characteristics; Chromatin; Chromatin Remodeling Factor; Co-Immunoprecipitations; Complex; Cytogenetics; Data; Dependence; Development; Epigenetic Process; Future; Gene Activation; Gene Cluster; Gene Expression; Gene Expression Profile; Genes; Goals; High Prevalence; Knock-out; Lead; Leukemic Cell; Link; MEIS1 gene; MLL gene; MLLT2 gene; Menin; Molecular; Mutate; Mutation; NPM1 gene; Oral; Phase I Clinical Trials; Process; Proteins; Research; Research Project Grants; Role; Site; Subgroup; Tertiary Protein Structure; Therapeutic; Therapeutic Effect; Transcription Coactivator; Transcriptional Regulation; Up-Regulation; epigenetic regulation; epigenetic therapy; histone methyltransferase; human model; improved; in vivo; inhibitor/antagonist; insight; leukemia; leukemic transformation; leukemogenesis; mouse model; mutant; novel; nucleophosmin; programs; promoter; recruit; self-renewal; small molecule inhibitor; stem-like cell; targeted treatment; therapeutic target; treatment strategy

Project Summary/Abstract Nucleophosmin (NPM1) mutations are among the most common aberrations in acute myeloid leukemia (AML) and cause a characteristic stem cell-like gene expression pattern including the upregulation of HOXA/B cluster genes and their co-factors MEIS1. The molecular mechanisms of how NPM1c mutations regulate this aberrant gene expression program remains poorly understood and there are currently no targeted therapy options available. We have recently found that NPM1c mutant leukemias depend on the histone methyltransferase MLL and its adaptor protein Menin to maintain leukemia gene expression and proliferation. The interaction between Menin and MLL is essential for the recruitment of the MLL complex to a subgroup of its target genes, such as MEIS1, which are in turn essential for maintaining leukemic self-renewal. Therapeutic targeting of the Menin- MLL interaction with small molecule inhibitors causes a loss of self-renewal and differentiation of NPM1c leukemia cells. The link between NPM1c mutations and the MLL-complex remains to be resolved. In the proposed project, we will develop a comprehensive understanding of the chromatin state that occurs in the presence of NPM1c specifically focusing on the role of Menin and MLL in this process. To achieve this, we will first determine the changes in chromatin state upon NPM1c degradation and determine essential protein domains of NPM1c (Aim 1). Next, we will identify which transcriptional activators and chromatin modifiers associate with the Menin-MLL complex in NPM1c mutant leukemias that lead to the aberrant target gene activation (Aim 2). Finally, we will focus on the chromatin binding factor LEDGF, which has been shown to associate with Menin-MLL and recruit transcriptional activators to control gene expression. Our preliminary data suggests that LEDGF is a dependency in NPM1c mutant leukemia cells and that LEDGF loss enhances the detrimental effects of Menin-inhibition on cell survival and MLL-target gene expression (Aim 3). In summary, the insights gained from the proposed project will help advance our mechanistic understanding of NPM1c driven leukemia development with the goal of improving treatment strategies in the future.

项目摘要/摘要 核素（NPM1）突变是急性髓样白血病（AML）中最常见的畸变之一 并引起特征性的干细胞样基因表达模式，包括Hoxa/b簇的上调 基因及其联合因素Meis1。 NPM1C突变如何调节这种异常的分子机制 基因表达计划仍然了解不足，目前尚无针对性的治疗选择 可用的。我们最近发现NPM1C突变体白血病依赖组蛋白甲基转移酶MLL 及其衔接蛋白梅宁（Menin）维持白血病基因表达和增殖。之间的相互作用 Menin和MLL对于将MLL复合物募集到其靶基因的亚组至关重要，例如 Meis1，这反过来又对维持白血病自我更新至关重要。 Menin的治疗靶向 与小分子抑制剂的MLL相互作用会导致NPM1C的自我更新和分化的损失 白血病细胞。 NPM1C突变与MLL复合物之间的联系仍有待解决。在 拟议的项目，我们将对发生在 NPM1C的存在专门针对Menin和MLL在此过程中的作用。为了实现这一目标，我们将 首先确定NPM1C降解后染色质状态的变化并确定必需蛋白 NPM1C的域（AIM 1）。接下来，我们将确定哪些转录激活剂和染色质修饰符 与NPM1C突变体白血病中的Menin-Mll复合物相关，导致异常靶基因 激活（目标2）。最后，我们将专注于染色质结合因子LEDGF，已显示为 与Menin-MLL和募集转录激活剂相关，以控制基因表达。我们的初步数据 表明LEDGF是NPM1C突变性白血病细胞的依赖性，而LEDGF损失增强了 梅宁抑制对细胞存活和MLL靶向基因表达的有害影响（AIM 3）。总而言之， 从提议的项目中获得的见解将有助于提高我们对NPM1C驱动的机械理解 白血病的发展旨在改善未来的治疗策略。