MEF2D-Mediated Transcriptional Control of Acute Myeloid Leukemia

MEF2D 介导的急性髓系白血病转录控制

• 批准号: 10365298
• 负责人: Rui Lu
• 金额: $ 35.61万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-20 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365298
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Adult; Affect; Biology; CEBPE gene; Cell Differentiation process; Cell Line; Cells; Child; Chimeric Proteins; Chromosomal translocation; Data; Defect; Dependence; Development; Differentiation and Growth; Disease; Disease Outcome; Drug resistance; Enhancers; Failure; Family member; Fusion Oncogene Proteins; Gene Expression; Gene Rearrangement; Gene Targeting; Genes; Genetic Predisposition to Disease; Genetic Transcription; Genome; Genomic approach; Goals; Growth; HOXA9 gene; Hematologic Neoplasms; Human; Knowledge; Laboratories; Leukemic Cell; Lymphoid; MLL gene; MLL-rearranged leukemia; Maintenance; Malignant Neoplasms; Mediating; Menin; Modeling; Molecular; Mus; Muscle Development; Myelogenous; Myeloid Progenitor Cells; Neurons; Normal Cell; Oncogenic; Output; Pathogenesis; Pathway interactions; Patients; Play; Prognosis; Proteins; Recurrence; Regulation; Relapse; Research; Resistance; Role; Sampling; Signal Transduction; Testing; Therapeutic; Tissues; Transcriptional Regulation; Vertebrates; Work; acute myeloid leukemia cell; base; cell growth; chemotherapy; comparative; gene repression; hematopoietic differentiation; improved; improved outcome; in vitro Model; in vivo; inhibitor; innovation; insight; leukemia; leukemogenesis; mouse model; muscle enhancer factor-2A; myocyte-specific enhancer-binding factor 2; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; paralogous gene; preclinical efficacy; programs; protein complex; protein expression; protein function; self-renewal; targeted treatment; transcription factor; treatment response; tumor

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) with MLL (KMT2A) gene rearrangement (MLL-r) is an aggressive disease with uncontrolled proliferation of myeloid progenitor cells and a failure of proper cell differentiation. Despite conventional chemotherapy, the overall survival of MLL-r AML remains poor and therapeutic options are limited, highlighting an unmet need to understand MLL-r AML pathogenesis and discover new genetic vulnerabilities. MEF2 transcriptional factors (MEF2A, 2B, 2C, and 2D) play important functions in the development of muscle, neuronal, and lymphoid lineages. Despite the known role of MEF2C as a direct MLL-r target essential for leukemogenesis, it remains unknown whether additional MEF2 family members are deregulated or involved in MLL-r leukemia. In this study, we identified that MEF2D gains aberrant super-enhancers and is highly upregulated in MLL-r AML. We demonstrate that MEF2D is selectively required for MLL-r AML, and depletion of MEF2D results in profound leukemia differentiation through transcriptional repression of CEBPE. We further show the MEF2D-CEBPE axis is critically involved in the anti-leukemia effects of DOT1L and Menin inhibitors. Furthermore, we discovered a novel interdependency of MEF2 paralogs in MLL-r AML. These preliminary data have provided us scientific rationale and enthusiasm for our central hypothesis that MEF2D, a novel transcriptional dependency highly expressed in MLL-r AML, maintains leukemia through inhibition of a CEBPE- centered myeloid differentiation program. This hypothesis is supported by extensive preliminary data and will be further tested by two specific aims: (1) establish the oncogenic function of MEF2D in MLL-r leukemogenesis and therapeutic response, and (2) investigate the mechanisms of MEF2D-mediated oncogenic regulation in MLL-r AML. In Specific Aim 1, we will determine the role of MEF2D in our pre-established genetically defined AML mouse models in vitro and in vivo; we will also evaluate the role of MEF2D-CEBPE axis in Menin inhibitor- mediated anti-leukemia effects. In Specific Aim 2, we will determine the molecular mechanisms by which MEF2D represses CEBPE, define MEF2D target genes using unbiased genome approaches, and evaluate the role of MEF2D-MEF2C interaction in MLL-r AML. The long-term goal of this project is to understand the MEF2 regulatory network in MLL-r AML, and to develop novel therapeutic approaches targeting oncogenic MEF2 factors for leukemia therapy. The main objective of this proposal is to establish the oncogenic function of MEF2D and determine how it regulates leukemia cell self-renewal and differentiation. Results from this proposal will provide significant new knowledge on the critical role of MEF2D in AML, reveal a new mechanism for suppression of normal hematopoietic differentiation in leukemia, and serve as the basis for targeting MEF2-related pathways as a potential therapeutic strategy for AML patients.

项目总结/摘要 伴有MLL（KMT 2A）基因重排（MLL-r）的急性髓性白血病（AML）是一种侵袭性疾病， 骨髓祖细胞的不受控制的增殖和正常细胞分化的失败。尽管 常规化疗，MLL-r AML的总体生存率仍然很差，治疗选择有限， 强调了理解MLL-r AML发病机制和发现新的遗传脆弱性的未满足的需求。 MEF 2转录因子（MEF 2A、2B、2C和2D）在肌肉发育中发挥重要作用， 神经元和淋巴谱系。尽管已知MEF 2C作为MLL-r的直接靶点的作用， 然而，对于白血病的发生，MEF 2家族的其他成员是否被解除调节或参与白血病的发生仍然是未知的。 MLL-r白血病。在这项研究中，我们发现MEF 2D获得异常的超级增强子，并且高度表达。 在MLL-r AML中上调。我们证明了MEF 2D是MLL-r AML选择性所需的，并且MEF 2D的缺失是MLL-r AML选择性所需的。 MEF 2D通过CEBPE的转录抑制导致白血病的深度分化。我们进一步 显示MEF 2D-CEBPE轴与DOT 1 L和Menin抑制剂的抗白血病作用密切相关。 此外，我们在MLL-r AML中发现了MEF 2旁系同源物的新的相互依赖性。这些初步数据 为我们的核心假设提供了科学依据和热情，即MEF 2D，一种新的 在MLL-r AML中高度表达的转录依赖性，通过抑制CEBPE- 中心骨髓分化计划。这一假设得到了广泛的初步数据的支持， 通过两个特定目的进一步测试：（1）确定MEF 2D在MLL-r白血病发生中的致癌功能， 治疗反应，和（2）研究MLL-r中MEF 2D介导的致癌调控机制 急性髓细胞白血病在具体目标1中，我们将确定MEF 2D在我们预先确定的基因定义的AML中的作用。 体外和体内小鼠模型;我们还将评估MEF 2D-CEBPE轴在Menin抑制剂中的作用- 介导的抗白血病作用。在具体目标2中，我们将确定MEF 2D 抑制CEBPE，使用无偏基因组方法定义MEF 2D靶基因，并评估 MLL-r AML中的MEF 2D-MEF 2C相互作用。该项目的长期目标是了解MEF 2监管 网络，并开发靶向致癌MEF 2因子的新治疗方法， 白血病治疗本提案的主要目的是确定MEF 2D的致癌功能， 确定它如何调节白血病细胞的自我更新和分化。该提案的结果将提供 关于MEF 2D在AML中的关键作用的重要新知识，揭示了抑制AML的新机制。 白血病中的正常造血分化，并作为靶向MEF 2相关途径的基础， AML患者的潜在治疗策略。