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The Role of the CBFB-MYH11 Complex in Leukemia Maintenance

CBFB-MYH11 复合物在白血病维持中的作用

基本信息

批准号：
10377387
负责人：
Ricia Katherine Hyde
金额：
$ 37.31万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377387
关键词：
Acute Myelocytic Leukemia Address Affect Allogenic Apoptosis Binding Biology Bone Marrow CBFB gene CBFbeta-MYH11 fusion protein Cells Chimeric Proteins Chromosomal Rearrangement Chromosome 16 Chromosome inversion Clinical Co-Immunoprecipitations Combined Modality Therapy Complex Core-Binding Factor DNA DNA Binding Dasatinib Development Disease Drug Targeting Event Family Family member Gene Expression Gene Fusion Genes Genetic Genetic Transcription Goals Growth HDAC1 gene Hematopoiesis Hematopoietic Stem Cell Transplantation Hematopoietic stem cells High Dose Chemotherapy In Vitro Knock-in Mouse Lead Leukemic Cell Life MYH11 gene Maintenance Malignant Neoplasms Modeling Molecular Molecular Target Mus Mutate Mutation Myelogenous Myeloid Cells Oncogenes Outcome Pathway interactions Patient-Focused Outcomes Patients Perception Pharmaceutical Preparations Pharmacology Prognostic Marker Protein Tyrosine Kinase Proteins RUNX1 gene Recurrence Relapse Repression Role Smooth Muscle Myosins Testing Toxic effect Transcriptional Activation Tumor Suppressor Genes Work acute myeloid leukemia cell base chimeric gene dimer driver mutation experience experimental study fusion gene gain of function genetic testing hematopoietic differentiation improved improved outcome in vivo inhibitor insight knock-down leukemia mouse model neoplastic new therapeutic target novel novel therapeutics patient derived xenograft model protein complex relapse patients side effect small hairpin RNA standard care therapy outcome tool transcription factor

项目摘要

ABSTRACT The long-term goal of our lab is to understand the role of the Core Binding Factor (CBF) family of transcription factors in acute myeloid leukemia (AML). CBF family members, which include RUNX1 and its binding partner CBFB, are the most frequently mutated genes in leukemia. One of the most common recurrent CBF mutations is the fusion gene CBFB-MYH11 (CM), which is generated by of the inversion of chromosome 16 [inv(16)]. Expression of CM is the initiating event in AML development, but additional cooperating mutations, such as activating mutations in the tyrosine kinase KIT, are required for transformation to a frank leukemia. CM is assumed to also be required after the acquisition of cooperating mutations, but its role during leukemia maintenance is currently poorly understood. CM was originally thought to dominantly repress RUNX1, leading to the repression of tumor suppressor genes. Our recent work supports a new model of the fusion protein’s activity: CM and RUNX1 together activate transcription of pro-leukemic genes. This new model implies that identifying the functionally important targets genes of the fusion protein complex may lead to new potential drug targets. Another extension of this new model is that there may be additional co-factors required for CM’s transcriptional activity. In recent work, we found that Histone Deacetylase 1 (HDAC1) is part of the CM/RUNX1 complex, and is required for expression of CM target genes. Using a mouse model of inv(16) AML, we found that the HDAC1 inhibitor entinostat induced differentiation, and reduced leukemic burden in vivo. Based on our previous work, we hypothesize that CM is required for the expression of genes that promote leukemia maintenance, and that HDAC1 is an important co-factor of CM. Consequently, we propose that HDAC1 inhibitors will be particularly useful for the treatment of inv(16) AML. In Specific Aim 1, we will use two complimentary approaches to define the role of CM in leukemia maintenance: a new knockin mouse model that allows for deletion of the fusion gene after leukemia development, and an inducible shRNA knockdown model. We will use these tools to determine CM’s role during leukemia maintenance in vivo, if CM independent cells can give rise to relapse, and test the role of candidate CM target genes in leukemia maintenance. In Specific Aim 2, we will determine the requirement for HDAC1 in CM+ leukemia cells, test whether HDAC1 affects expression of both CM target and non-target genes, and test potential mechanisms for HDAC1’s non-canonical role in transcriptional activation. Specific Aim 3 will test the potential of the entinostat to treat inv(16) AML. We will use genetic and patient derived xenograft mouse models to test whether the addition of entinostat to the standard treatments will reduce leukemic burden and increase survival. We will also test whether using entinostat to inhibit CM in combination with dasatinib to inhibit cooperating mutations in KIT is more effective than either drug alone. The proposed studies are based on our accumulated experience and our strong preliminary findings, and will address important gaps in the field and have direct translational implications for inv(16) AML patients.

摘要我们实验室的长期目标是了解核心结合因子（CBF）家族在细胞凋亡中的作用。急性髓细胞白血病（AML）的治疗。CBF家族成员，包括RUNX 1及其结合伴侣CBFB是白血病中最常见的突变基因。最常见的复发性 CBF突变是由染色体倒位产生的融合基因CBFB-MYH 11（CM 16 [inv（16）]。CM的表达是AML发展的起始事件，但其他协同突变，如酪氨酸激酶KIT中的激活突变，是转化为明显白血病所必需的。CM 假设在获得协同突变后也需要，但其在白血病中的作用目前对维护的了解很少。CM最初被认为主要抑制RUNX 1，肿瘤抑制基因的抑制。我们最近的工作支持了融合蛋白的新模型活性：CM和RUNX 1共同激活促白血病基因的转录。这一新模式意味着，鉴定融合蛋白复合物的功能重要的靶基因可能导致新的潜在药物目标的这个新模型的另一个扩展是CM可能需要额外的辅因子转录活性在最近的工作中，我们发现组蛋白去乙酰化酶1（HDAC 1）是CM/RUNX 1的一部分，复杂，并且是CM靶基因表达所必需的。使用inv（16）AML小鼠模型，我们发现 HDAC 1抑制剂恩替司他诱导分化，并降低体内白血病负荷。根据我们之前的工作，我们假设CM是促进基因表达所必需的。 HDAC 1是CM的重要辅助因子。因此，我们建议HDAC 1 抑制剂将特别适用于治疗inv（16）AML。在具体目标1中，我们将使用互补的方法来确定CM在白血病维持中的作用：一种新的敲入小鼠模型，允许在白血病发展后缺失融合基因，以及可诱导的shRNA敲低模型。我们将使用这些工具来确定CM在体内白血病维持过程中的作用，如果CM非依赖性细胞可以引起复发，并测试候选CM靶基因在白血病维持中的作用。在特定目的2，我们将确定CM+白血病细胞对HDAC 1的需求，测试HDAC 1是否影响CM+白血病细胞对HDAC 1的依赖性。 CM靶基因和非靶基因的表达，并测试HDAC 1非经典的潜在机制在转录激活中的作用。具体目标3将测试恩替司他治疗inv（16）AML的潜力。我们将使用遗传和患者来源的异种移植小鼠模型来测试是否将恩替司他添加到标准治疗将减少白血病负担并提高存活率。我们还将测试是否使用恩替司他与达沙替尼联合抑制CM以抑制KIT中的协同突变，药物单独拟议的研究是基于我们积累的经验和我们强有力的初步发现，并将解决该领域的重要空白，并对inv（16）AML患者具有直接的翻译意义。