MLL Family Histone Methyltransferases in Myeloid Leukemia

髓系白血病中的 MLL 家族组蛋白甲基转移酶

• 批准号: 10406930
• 负责人: Patricia Ernst
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406930
• 关键词: Acute Myelocytic Leukemia; Adult; Affect; Animal Model; Area; Biochemical; Biological; CRISPR/Cas technology; Child; Chimeric Proteins; Chromatin; Chromosome 19; Clinical Trials; Collaborations; Complement; Confusion; Cytogenetics; Data; Dependence; Development; Diagnosis; Down-Regulation; Drug Targeting; Enzymes; Epigenetic Process; Experimental Leukemia; Family; Fusion Oncogene Proteins; Gene Family; Genes; Genetic Transcription; Growth; Heterogeneity; Histone H3; Histones; Human; Human Chromosomes; IL3 Gene; ITGB3 gene; Impairment; In Vitro; Interleukin-3 Receptor; Kabuki Make-Up Syndrome; Knock-out; Lymphoma; Lysine; MLL gene; MLL-AF6; MLL-AF9; MLL2 gene; Malignant Neoplasms; Mediating; Metabolic; Methylation; Methyltransferase; Modeling; Molecular; Mus; Mutate; Mutation; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; Nature; Nomenclature; Oncogenes; Oncoproteins; Outcome; Pathway interactions; Patients; Play; Proteins; Research; Role; Sampling; Scanning; Signal Transduction; Survival Rate; System; Testing; Therapeutic; Toxic effect; Transferase; Translating; United States; Work; acute myeloid leukemia cell; cancer type; cell transformation; cell type; chemotherapy; clinically relevant; drug sensitivity; effective therapy; epigenomics; experimental study; genome-wide; genomic data; histone methyltransferase; in vivo; inhibitor; leukemia; leukemogenesis; molecular subtypes; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; paralogous gene; preclinical study; promoter; role model; self-renewal; stemness; targeted treatment; transcriptome

PROJECT SUMMARY Despite some remarkable advances in treating certain types of cancer, the nature of mutations and heterogeneity of acute myeloid leukemia (AML) have made this cancer challenging to treat successfully. Genomic data have suggested many new therapeutic targets, but even successful molecular inhibition does not always translate to effective therapy, justifying a broader understanding of mechanisms and pathways altered in AML. Our recent studies illuminated a novel pathway by which the endogenous MLL1 and MLL2 histone methyltransferases contribute to leukemogenesis driven by MLL fusion oncoproteins. In MLL-AF9 or MLL-AF6-driven AML, we found that the endogenous MLL2 histone methyltranferase played a major role in sustaining several coordinated pathways that enhance leukemia survival and proliferation. Although MLL1 did not contribute on its own to leukemogenesis, it collaborated with MLL2 in regulating critical AML survival/proliferation pathways affecting NFκB, integrin β3 and IL-3 signaling. Given the widespread reliance on all three of these pathways for AML survival/proliferation, we propose to test the role and downstream pathways regulated by MLL1 and MLL2 in a variety of genetically defined AML animal models, as well as human leukemia lines and primary samples. Specifically, our proposal aims to 1) determine whether loss of MLL1/MLL2 or both affects AML driven by a variety of genetically-defined murine AML models, 2) identify MLL1/MLL2 regulated pathways in human AML cells along with the domains within MLL2 that contribute regulating these pathways, and 3) define the transcriptome perturbations, epigenomic states, and effect of both Mll1 and Mll2 knockout in MLL-AF9-driven AML and determine the mechanism by which they collaborate to support AML survival. These experiments will identify epigenetic vulnerabilities that may be particular to certain cytogenetic subtypes of AML or may be broadly relevant.

项目概要 尽管在治疗某些类型的癌症方面取得了一些显着的进展，但突变的本质 急性髓系白血病 (AML) 的异质性和异质性使得这种癌症的治疗具有挑战性 成功地。基因组数据提出了许多新的治疗靶点，但即使是成功的 分子抑制并不总能转化为有效的治疗，因此需要更广泛的治疗 了解 AML 中改变的机制和途径。我们最近的研究阐明了 内源性 MLL1 和 MLL2 组蛋白甲基转移酶贡献的新途径 MLL 融合癌蛋白驱动的白血病发生。在 MLL-AF9 或 MLL-AF6 驱动的 AML 中，我们 发现内源性 MLL2 组蛋白甲基转移酶在维持 增强白血病存活和增殖的几种协调途径。虽然MLL1 它本身并不促进白血病发生，它与 MLL2 合作调节关键的 影响 NFκB、整合素 β3 和 IL-3 信号传导的 AML 存活/增殖途径。鉴于 由于 AML 生存/增殖广泛依赖所有这三种途径，我们建议 测试 MLL1 和 MLL2 在多种遗传物质中的作用和下游通路的调节 定义了 AML 动物模型，以及人类白血病细胞系和原始样本。 具体来说，我们的建议旨在 1) 确定 MLL1/MLL2 或两者的丢失是否会影响 AML 由多种基因定义的小鼠 AML 模型驱动，2) 识别 MLL1/MLL2 调节 人类 AML 细胞中的通路以及 MLL2 内有助于调节的结构域 这些途径，以及 3) 定义了转录组扰动、表观基因组状态和 MLL-AF9 驱动的 AML 中的 Mll1 和 Mll2 敲除，并确定其机制 他们合作支持 AML 的生存。这些实验将鉴定表观遗传 可能是 AML 某些细胞遗传学亚型特有的脆弱性，也可能是广泛存在的 相关的。

项目成果

Hematopoietic transformation in the absence of MLL1/KMT2A: distinctions in target gene reactivation.

MLL1/KMT2A 缺失下的造血转化：靶基因重新激活的差异。

• DOI: 10.1080/15384101.2019.1618642
• 发表时间: 2019
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: Chen,Yufei;Ernst,Patricia
• 通讯作者: Ernst,Patricia

Menin is necessary for long term maintenance of meningioma-1 driven leukemia.

• DOI: 10.1038/s41375-021-01146-z
• 发表时间: 2021-05
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Libbrecht C;Xie HM;Kingsley MC;Haladyna JN;Riedel SS;Alikarami F;Lenard A;McGeehan GM;Ernst P;Bernt KM
• 通讯作者: Bernt KM