Role of BAZ2A in MLL-r leukemia and therapeutic response

BAZ2A 在 MLL-r 白血病中的作用和治疗反应

• 批准号: 10593927
• 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: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593927
• 关键词: Achievement; Acute leukemia; Affect; Biochemical; Cell Line; Cell Nucleus; Chromatin; Classification; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Elements; Epigenetic Process; Future; Gene Expression; Gene Expression Regulation; Gene Rearrangement; Genetic Screening; HDAC4 gene; Histone Deacetylation; Histone H3; Human; In Vitro; Libraries; Lysine; MLL gene; MLL-rearranged leukemia; Malignant Neoplasms; Mediating; Methyltransferase; Mutagenesis; Oncogenes; PHD Finger; Patients; Pharmacologic Substance; Phase I Clinical Trials; Prognosis; Proteins; Publishing; RNA Interference; Reader; Regimen; Research; Ribosomal DNA; Ribosomal RNA; Role; SIRT1 gene; Scanning; Survival Rate; Techniques; Technology; Tertiary Protein Structure; Therapeutic; Validation; Work; World Health Organization; antileukemic activity; cancer therapy; cancer type; chromatin remodeling; clinically relevant; efficacy evaluation; epigenetic silencing; functional genomics; genetic approach; genome-wide; genomic locus; improved; in vivo; inhibitor; innovation; insight; knock-down; leukemia; leukemogenesis; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; pharmacologic; pre-clinical; programs; response; small hairpin RNA; targeted treatment; therapeutic gene; 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 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.

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 组蛋白 H3 赖氨酸 79 (H3K79) 甲基转移酶 DOT1L 在 MLL-r 白血病发生中发挥核心作用。 DOT1L 抑制剂作为单一药物治疗已引起重要的临床反应，但是， 预计联合治疗是必要的。 我们基于 MLL-r 白血病 DOT1L 抑制剂致敏筛选的初步研究已经确定 BAZ2A 的抑制显着增加 DOT1L 抑制剂的抗白血病活性。目标 该应用的目的是确定介导 SIRT1 可用性的关键表观遗传机制 抑制 MLL-r 白血病中的癌基因表达。我们的中心假设是 BAZ2A，一种染色质 rDNA 位点的重塑蛋白，介导 SIRT1 的重新分布以实现组蛋白脱乙酰化和沉默 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 联合疗法的功效（目标 2），并验证新的饱和度 CRISPR 蛋白扫描技术从头发现 DOT1L 和 BAZ2A 中的功能元件 （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 表观遗传网络的组成部分可以有效地抑制癌症程序，并且（2）它建立了一个 用于亚蛋白水平功能域发现的全新遗传筛选方法。这的影响 研究将具有重要意义，因为（1）它立即提供了新的治疗机会 对抗难以治疗的 MLL-r 白血病，(2) 它将有助于识别新的功能元件 用于未来药物靶向的表观遗传调节剂。

项目成果

ACTR5 controls CDKN2A and tumor progression in an INO80-independent manner.

ACTR5 以独立于 INO80 的方式控制 CDKN2A 和肿瘤进展。

• 发表时间: 2022-12-23
• 影响因子: 13.6
• 作者: Xu, Xiaobao;Chan, Anthony K N;Li, Mingli;Liu, Qiao;Mattson, Nicole;Pangeni Pokharel, Sheela;Chang, Wen;Yuan, Yate;Wang, Jinhui;Moore, Roger E;Pirrotte, Patrick;Wu, Jun;Su, Rui;Müschen, Markus;Rosen, Steven T;Chen, Jianjun;Yang, L
• 通讯作者: Yang, L