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：
10599919
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/10599919
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 Heterodimerization High Dose Chemotherapy Histone Deacetylase Inhibitor In Vitro Knock-in Mouse 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 Prognostic Marker Protein Tyrosine Kinase Proteins RUNX1 gene Recurrence Relapse Repression Role Testing Toxic effect Transcriptional Activation Tumor Suppressor Genes Work acute myeloid leukemia cell chimeric gene cofactor driver mutation experience experimental study fusion gene gain of function 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 pharmacologic 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.

抽象的长期目标或实验室是了解核心结合因子（CBF）家族的作用急性髓样白血病（AML）中的转录因子。结合伴侣CBFB是白血病中最常见的基因。 CBF突变是融合基因基因CBFB-MYH11（CM），它是由染色体反转产生的 16 [Inv（16）] CM的表达是AML开发中的启动事件例如在酪氨酸激酶试剂盒中激活突变，需要转化为弗兰克白血病假定在获得合作突变后也需要，但在白血病中起作用维护目前较差的莱（Ley）理解。抑制肿瘤抑制基因。活性：CM和Runx1一起激活促美基因的转录。识别融合蛋白复合物的功能重要靶标基因可能会导致量身药物目标的另一个扩展名是CM所需转录活动。复合物，是CM靶基因的表达。 thit hDAC1抑制剂entinostat Indukemic Burden in Vivo。基于我们以前的工作，我们假设CM是促进基因的表达白血病维持，HDAC1是CM的重要副因素。抑制剂对于特定目标1的teations（16）尤其有用。定义CM在白血病主体中的作用的免费方法：一种新的敲击声音在白血病发育后允许融合基因和诱导型shRNA敲低模型。如果CM独立单元格可以引起复发，并在特异性中测试候选CM靶基因在白血病维持中的作用 AIM 2，我们将确定CM+白血病细胞中HDAC1的需求，测试HDAC1是否影响 CM靶标和非目标基因的表达，以及HDAC1非Cannascal的潜在机制在转录激活中的作用将使用遗传和患者衍生的异种移植小鼠模型测试是否在标准信托将减少白血病负担并增加生存率。抑制CM与dasatinib结合以抑制套件中的合作突变比任何一个都更有效仅药物。并将解决该领域的重要差距，并为INV（16）AML患者进行直接翻译翻译。