Mechanism and therapeutic opportunities of targeting the Tudor domain

针对 Tudor 结构域的机制和治疗机会

• 批准号: 10606365
• 负责人: Chun-Wei David Chen
• 金额: $ 51.09万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606365
• 关键词: Acetylation; Achievement; Acute leukemia; Affect; Animals; Arginine; Binding; Biochemical; Bromodomain; CRISPR library; CRISPR screen; Cell Line; Cells; Classification; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Combined Modality Therapy; Complex; Elements; Epigenetic Process; Future; Gene Expression; Gene Expression Regulation; Gene Rearrangement; Genes; Genetic; Genetic Screening; Goals; Histone Acetylation; Histone Deacetylation; Histone H3; Histones; Human; Infant Leukemia; Lead; Left; Lysine; MLL gene; MLL-AF9; MLL-rearranged leukemia; Maintenance; Malignant Neoplasms; Mediating; Methylation; Methyltransferase; Monitor; Nature; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmacologic Substance; Phase I Clinical Trials; Positioning Attribute; Prognosis; Proteins; Publishing; Reader; Regimen; Reporting; Research; Role; SAGA; SIRT1 gene; Scanning; Signal Transduction; Surface; Survival Rate; Tail; Technology; Therapeutic; Toxic effect; Transcriptional Activation; Work; World Health Organization; cancer type; chromatin modification; clinically relevant; combinatorial; drug discovery; genetic approach; genome-wide; histone acetyltransferase; histone methylation; improved; in vivo; inhibitor; innovation; insight; leukemia; leukemogenesis; multiple omics; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; pharmacologic; pre-clinical; programs; protein folding; recruit; response; 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 Tudor domain focused CRISPR screen in MLL-r leukemia identified SGF29 as a novel vulnerability in MLL-r leukemia. The objective of this application is to determine the critical epigenetic mechanisms that mediate the availability of KAT2A/B to maintain H3K9ac and oncogene expression in MLL-r leukemia. Our central hypothesis is that SGF29, an H3K4me3 reader protein, mediates recruitment of KAT2A/B to maintain histone H3K9ac and MYC oncogenic program in MLL-r leukemia. We will dissect the SGF29-mediated epigenetic mechanisms (Aim 1) and investigate the efficacy of SGF29 targeting (alone or in combination with DOT1L inhibition) as a novel therapy in MLL-r leukemia (Aim 2). 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 pocket and drug 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 我们的初步研究基于MLL-r白血病中的Tudor结构域聚焦CRISPR筛选， SGF 29是MLL-r白血病的一个新的脆弱性。本申请的目的是确定关键的 介导KAT 2 A/B可用性以维持H3 K9 ac和癌基因表达的表观遗传机制 MLL-r白血病我们的中心假设是，SGF 29，一种H3 K4 me 3阅读蛋白，介导募集 KAT 2A/B的表达在MLL-r白血病中维持组蛋白H3 K9 ac和MYC致癌程序。我们将解剖 SGF 29介导的表观遗传机制（目的1），并研究SGF 29靶向（单独或联合） 联合DOT 1 L抑制）作为MLL-r白血病的新疗法（目的2）。 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 为亚蛋白水平的功能口袋和药物发现提供了全新的遗传筛选方法。的影响 这项研究的意义在于：（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， 用于未来药物靶向的表观遗传调节剂。