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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要尽管在治疗某些类型的癌症方面取得了显着进步，但突变的性质急性髓样白血病（AML）的异质性已提出了治疗的癌症挑战成功地。基因组数据提出了许多新的治疗靶标，但即使成功分子抑制并不总是转化为有效的疗法，证明更广泛的合理性对AML中机制和途径的理解。我们最近的研究照亮了内源性MLL1和MLL2 Hisstone甲基转移酶贡献的新型途径由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 Hisstone甲基转移酶在维持虽然mll1 它没有自行为白血病生成做出贡献，而是与MLL2合作在监管关键方面影响NFκB，整联蛋白β3和IL-3信号传导的AML存活/增殖途径。鉴于在所有这三种途径上保留AML存活/增殖的所有三种途径，我们建议测试由MLL1和MLL2调节的角色和下游途径定义的AML动物模型以及人类白血病系和主要样品。具体而言，我们的建议旨在1）确定MLL1/MLL2或两者的丢失是否影响AML 在各种普遍定义的鼠AML模型的驱动下，2）识别受调节的MLL1/MLL2 人类AML细胞中的途径以及MLL2内的域的途径这些途径，以及3）定义转录组扰动，表观基因组状态以及 MLL-AF9驱动的AML中的MLL1和MLL2敲除，并确定该机制他们合作以支持AML生存。这些实验将识别表观遗传学 AML的某些细胞遗传学亚型可能特定的脆弱性或可能广泛相关的。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.)
影响因子：
0
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