Dependency of AML on CARM1 activity

AML 对 CARM1 活性的依赖性

• 批准号: 10663945
• 负责人: Stephen D. Nimer
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663945
• 关键词: AML1-ETO fusion protein; Acute Myelocytic Leukemia; Affect; Arginine; Blood Cells; Cancer Cell Growth; Cancer Patient; Cell Death; Cell Differentiation process; Cell Line; Cell Survival; Cells; ChIP-seq; Chromatin Remodeling Factor; Co-Immunoprecipitations; Combined Modality Therapy; Cytoplasm; Dependence; Development; Disease; Engraftment; Enzymes; Epigenetic Process; Genes; Genetic; Genetic Transcription; Goals; Hematopoietic; Hematopoietic stem cells; Histones; Human; Human Cell Line; JAK2 gene; Knock-out; Malignant Neoplasms; Mass Spectrum Analysis; Messenger RNA; Methylation; Modeling; Modification; Molecular; Mutation; Myelogenous; NOD/SCID mouse; Nuclear; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Pre-Clinical Model; Predisposition; Proliferating; Protein-Arginine N-Methyltransferase; Proteins; RUNX1 gene; Regulation; Role; Sampling; Signal Transduction; Specificity; Survival Rate; System; Techniques; Testing; Therapeutic; Toxic effect; Tyrosine; Up-Regulation; acute myeloid leukemia cell; cancer cell; cancer type; cell growth; cell type; coactivator-associated arginine methyltransferase 1; effective therapy; experimental study; improved; inhibitor; insight; knock-down; leukemia; metaplastic cell transformation; mouse model; non-histone protein; novel; posttranscriptional; protein protein interaction; resistance mechanism; small molecule inhibitor; targeted cancer therapy; targeted treatment; therapeutically effective; therapy development; transcription factor; transcriptome sequencing

Project Summary/ Abstract Defining the genetic and epigenetic abnormalities that drive cellular transformation has provided insights into potential therapeutic approaches to cancer. However, the myriad of genetic changes that accompany specific types of cancer makes it difficult to find therapeutic approaches applicable to the bulk of patients with a given disease. We have identified an oncogenic role for the epigenetic enzyme “co-activator associated arginine methyltransferase 1” (CARM1) in AML, and a dependency of AML cells, but not normal hematopoietic stem cells, on CARM1 activity. CARM1 methylates a variety of histone and non-histone substrates and targeting its activity, via small molecule inhibitors, knockdown (KD) or knockout (KO) approaches, triggers AML cell differentiation and death. The proposed studies represent a conceptual shift from targeting specific mutations found in AML to developing therapies that target chromatin modifiers and transcriptional regulators that are essential to large numbers of AML patients. To advance this new paradigm we have proposed the following specific aims: Aim 1: We will define the molecular basis for the differentiation-promoting effects of CARM1 inhibition on AML cells, identifying the critical CARM1-interacting proteins, substrates and target genes that regulate myeloid differentiation, proliferation and survival. We will use state-of- the-art techniques including the BioID2 system, mass-spectrometry, RNA-Seq and ChIP-Seq. Aim 2: We will determine the mechanisms that control the level of CARM1 activity in AML cells, defining how changes in CARM1 mRNA levels, protein levels, and post- transcriptional modifications, including phosphorylation, affect CARM1 activity in AML cells. Aim 3: Determine the basis for the unique sensitivity of AML cells to CARM1 inhibition or KD. We will also define CARM1 inhibitor resistance mechanisms, and test CARM1 inhibitor-containing combination therapies, using human AML cell lines and primary AML samples and NOD/SCID mice engrafted with human AML cells. These studies will help establish the importance of CARM1 in the pathogenesis of AML, and advance our understanding of how CARM1 inhibitors can be used as part of an effective and novel “epigenetic-targeted” strategy for treating cancer.

项目摘要/摘要 定义驱动细胞转化的遗传和表观遗传异常 对潜在的癌症治疗方法的见解。但是，无数遗传变化 适应特定类型的癌症使得很难找到治疗方法 适用于大部分给定疾病的患者。我们已经确定了致癌作用 表观遗传酶“共激活因子相关的精氨酸甲基转移酶1”（CARM1），AML， AML细胞的依赖性（但不是正常的造血干细胞）对CARM1活性的依赖性。 CARM1甲基化多种组蛋白和非固定基底物，并通过 小分子抑制剂，敲低（KD）或敲除（KO）接近，触发AML细胞 分化和死亡。拟议的研究代表了从靶向的概念转变 在AML中发现的特定突变，以开发针对染色质修饰剂和的疗法 转录调节剂对大量AML患者至关重要。推进这一点 新范式我们提出了以下特定目的： 目标1：我们将定义CARM1分化促进作用的分子基础 抑制AML细胞，鉴定关键的CARM1相互作用蛋白，底物和 调节髓样分化，增殖和存活的靶基因。我们将使用最新 艺术技术，包括Bioid2系统，质谱法，RNA-Seq和 chip-seq。目标2：我们将确定控制CARM1水平的机制 AML细胞的活性，定义CARM1 mRNA水平，蛋白水平和后的变化 转录修饰（包括磷酸化）会影响AML细胞中的CARM1活性。目的 3：确定AML细胞对CARM1抑制或KD的唯一灵敏度的基础。我们将 还定义CARM1抑制剂耐药机制，并测试含CARM1抑制剂 组合疗法，使用人AML细胞系和主要AML样品和点头/SCID 与人AML细胞接合的小鼠。这些研究将有助于确定Carm1的重要性 在AML的发病机理中，并促进了我们对CARM1抑制剂的理解 用作治疗癌症的有效且新颖的“表观遗传靶向”策略的一部分。