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The Role of CARM1-Dependent Arginine Methylation of BRD4 in Hematopoiesis

BRD4 的 CARM1 依赖性精氨酸甲基化在造血中的作用

基本信息

批准号：
10316159
负责人：
Adnan Kasim Mookhtiar
金额：
$ 3.8万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316159
关键词：
Acute Myelocytic Leukemia Affect Architecture Arginine Back Binding Binding Proteins Biological Blood Cells Bone Marrow Bromodomain C-terminal Cell Fractionation Cell Maintenance Cells ChIP-seq Chromatin Clinical Trials Clinical Trials Design Data Dependence Development Disease Disease model Disease remission Drug Targeting Enzymes Epigenetic Process Event Family Follow-Up Studies Gene Expression Genes Genetic Transcription Genomic approach Genomics Hematopoiesis Hematopoietic Neoplasms Hematopoietic stem cells Histones Human Impairment Leukemic Cell Lysine Maintenance Malignant - descriptor Malignant Neoplasms Mediating Methylation Microscopy Modification Movement Mus Mutate Myelogenous Oncogenic Outcome Pathogenesis Pathway interactions Patients Physiological Play Post-Translational Protein Processing Property Protein Family Protein-Arginine N-Methyltransferase Proteins Reader Regulation Relapse Role Series Signal Transduction System Techniques Tertiary Protein Structure Therapeutic Translations acute myeloid leukemia cell base cancer clinical trial cell growth chemotherapy clinically relevant coactivator-associated arginine methyltransferase 1 efficacy testing epigenomics functional genomics genetic regulatory protein improved inhibitor/antagonist insight knock-down leukemia leukemogenesis member mouse model mutant next generation sequencing non-histone protein novel novel therapeutics overexpression preclinical development protein function protein protein interaction small molecule small molecule inhibitor targeted treatment therapeutic target transcriptome sequencing tumorigenesis

项目摘要

ABSTRACT: Acute myeloid leukemia (AML) is an aggressive and lethal disease characterized by the accumulation of immature blood cells in the bone marrow. Epigenetic modifying proteins are emerging as important therapeutic targets in leukemia, as they are one of the most commonly mutated class of genes in de novo AML and are targetable with small molecules. Histone reader, bromodomain containing protein 4 (BRD4) and coactivator-associated arginine methyltransferase 1 (CARM1) have both been shown to have malignant functions in leukemia. Furthermore, perturbation of these proteins has demonstrated a therapeutic potential for the treatment of AML. Recently, focused efforts have been made to develop efficacious therapeutic drugs targeting these proteins and their associated pathways to treat AML. CARM1 inhibitors are being investigated in preclinical development, while several BET inhibitors are currently being investigated in clinical trials. Several studies have identified post translational modifications of BRD4 though the functional relevance of these modifications is poorly studied. Our preliminary findings identify a novel CARM1-dependent asymmetric arginine methylation of BRD4. Moreover, our data suggest a functional CARM1-BRD4 signaling axis in which CARM1 dimethylates BRD4, which results in the regulation of subcellular localization of BRD4 and its binding to the chromatin promoting its oncogenic functions. We propose to study the role of CARM1 in regulating BRD4 function in AML cells and to understand whether this post-translation modification of BRD4 is required for leukemia initiation and maintenance in mouse models of the disease. From our preliminary data we hypothesize that the CARM1-mediated arginine methylation of BRD4 increases its localization and binding to chromatin. Furthermore, perturbations of this methylation will result in an eviction of chromatin-bound BRD4, in turn leading to improved survival through the suppression of the transcription of oncogenic genes that drive AML pathogenesis. Though we have unearthed CARM1 as an efficacious target of AML and shown its beneficial effects on depleting oncogenic signaling, the precise mechanisms in which CARM1 inhibition hinders AML development still remains a question. By studying the substrates and interacting proteins of CARM1, such as BRD4, and defining its downstream biological events, we will more fully understand the cellular machinery that drives AML and more efficiently devise therapeutic strategies. We are confident that successful completion of our proposed study will provide experimental support for the advancement of both BET and CARM1 inhibitors as a treatment for AML as well as inform the development of novel AML targeted therapies.

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