Combinational targeting the feed forward epigenetic circuitry in mixed lineage leukemia

针对混合谱系白血病前馈表观遗传回路的组合

• 批准号: 10306337
• 负责人: Chun-Wei David Chen
• 金额: $ 39.57万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-03 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306337
• 关键词: Acetylation; Achievement; Acute leukemia; Affect; Binding; Biochemical Genetics; Biotin; Cell Line; ChIP-seq; Chimeric Proteins; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complex; Elements; Epigenetic Process; Exhibits; Future; Gene Cluster; Gene Expression; Gene Expression Regulation; Gene Rearrangement; Genes; Genetic Screening; Genetic Transcription; Histone Acetylation; Histone Deacetylation; Histone H3; Histones; Human; In Vitro; Left; Libraries; Lysine; MEIS1 gene; MLL gene; MLL-rearranged leukemia; Malignant Neoplasms; Mediating; Methylation; Methyltransferase; Mixed-Lineage Leukemia; Molecular; Mutagenesis; Oncogenes; PHD Finger; Patients; Peptides; Pharmacologic Substance; Pharmacology; Phase I Clinical Trials; Prognosis; Proteins; Publishing; Reader; Regimen; Research; Role; SIRT1 gene; Scanning; Survival Rate; Techniques; Technology; Tertiary Protein Structure; Therapeutic; Transcriptional Activation; Validation; Work; World Health Organization; base; cancer type; clinically relevant; density; efficacy evaluation; functional genomics; genetic approach; genome-wide; histone acetyltransferase; histone modification; improved; in vivo; inhibitor; innovation; leukemia; leukemogenesis; mutant; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; pre-clinical; programs; recruit; response; small hairpin RNA; targeted treatment; treatment response

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 have identified an essential role of the PHF20/KAT8 histone acetyltransferase complex, in supporting the expression of DOT1L-driven oncogenes. The objective of this application is to determine the critical epigenetic mechanisms that collaborate with DOT1L to maintain oncogene expression in MLL-r leukemia. Our central hypothesis is that PHF20 mediates KAT8 recruitment to maintain the locus-specific histone acetylation and transcription of the DOT1L-driven leukemic program. We will investigate the efficacy of DOT1L and PHF20/KAT8 combination therapies (Aim 1), dissect the PHF20/KAT8 chromatin targeting mechanisms (Aim 2), and validate a novel high-density CRISPR protein scan technology for de novo discovery of the functional elements in DOT1L/PHF20/KAT8 (Aim 3). This study is innovative because (1) it introduces a novel concept of simultaneously targeting multiple components of an epigenetic feed-forward loop 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.

项目概要/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。 MLL-r的临床需求未得到满足且缺乏有效的靶向治疗 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了一个核心 组蛋白 H3 赖氨酸 79 (H3K79) 甲基转移酶 DOT1L 在 MLL-r 白血病发生中的作用。重要的 已经注意到 DOT1L 抑制剂作为单一药物治疗的临床反应，但是，预计 联合治疗是必要的。 我们基于 DOT1L 抑制剂致敏筛选的初步研究已经确定了其重要作用 PHF20/KAT8 组蛋白乙酰转移酶复合物，支持 DOT1L 驱动的表达 癌基因。本应用的目的是确定关键的表观遗传机制 与 DOT1L 合作维持 MLL-r 白血病中的癌基因表达。我们的中心假设是 PHF20 介导 KAT8 招募以维持位点特异性组蛋白乙酰化和转录 DOT1L 驱动的白血病项目。我们将研究 DOT1L 和 PHF20/KAT8 的功效 联合疗法（目标 1），剖析 PHF20/KAT8 染色质靶向机制（目标 2），以及 验证一种新型高密度 CRISPR 蛋白扫描技术，用于从头发现功能性蛋白 DOT1L/PHF20/KAT8 中的元素（目标 3）。 这项研究具有创新性，因为（1）它引入了同时瞄准多个目标的新概念 表观遗传前馈循环的组成部分，可有效抑制癌症程序，以及（2） 建立了一种全新的基因筛选方法，用于亚蛋白水平功能域的发现。这 这项研究的影响将具有重要意义，因为（1）它立即提供了新的治疗方法 对抗难以治疗的 MLL-r 白血病的机会，(2) 它将有助于识别新的功能 用于未来药物靶向的表观遗传调节元件。