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: 10531876
• 负责人: Chun-Wei David Chen
• 金额: $ 38.78万
• 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/10531876
• 关键词: Acetylation; Achievement; Acute leukemia; Affect; Binding; Biochemical; Biotin; Cell Line; ChIP-seq; Chimeric Proteins; Chromatin; Classification; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; 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; 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; 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; pharmacologic; 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白血病发生中的作用。重要 已经注意到DOT 1 L抑制剂作为单一药剂治疗的临床应答，然而， 联合治疗是必要的 我们基于DOT 1 L抑制剂致敏筛选的初步研究已经确定了一个重要的作用， PHF 20/KAT 8组蛋白乙酰转移酶复合物，支持DOT 1 L驱动的表达， 致癌基因本申请的目的是确定关键的表观遗传机制， 与DOT 1 L合作维持MLL-r白血病中的癌基因表达。我们的核心假设是 PHF 20介导KAT 8募集以维持基因座特异性组蛋白乙酰化和转录， 由DOT 1 L驱动的白血病项目我们将研究DOT 1 L和PHF 20/KAT 8的疗效 联合治疗（目标1），剖析PHF 20/KAT 8染色质靶向机制（目标2）， 验证一种新的高密度CRISPR蛋白质扫描技术，用于从头发现功能性 DOT 1 L/PHF 20/KAT 8中的元素（目标3）。 这项研究是创新的，因为（1）它引入了同时靶向多个 表观遗传前馈回路的组成部分，以有效地抑制癌症程序，和（2）它 为亚蛋白水平的功能结构域发现建立了一种全新的遗传筛选方法。的 这项研究的影响将是有意义的，因为（1）它立即提供了新的治疗方法， 机会对难以治疗的MLL-r白血病，和（2）它将有助于确定新的功能 表观遗传调节因子用于未来的药物靶向。