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.

抽象的我们实验室的长期目标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。 CBF家庭成员，其中包括Runx1及其结合伴侣CBFB是白血病中最常见的突变基因。最常见的复发之一 CBF突变是融合基因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，但其他合作突变，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。厘米假定在获得合作突变后也需要，但其在白血病中的作用维护目前知之甚少。 CM最初被认为主要压制Runx1，领导表达肿瘤抑制基因。我们最近的工作支持融合蛋白的新模型活性：CM和RUNX1共同激活了血清学基因的转录。这个新模型意味着识别融合蛋白复合物的功能重要靶标基因可能导致新的潜在药物目标。该新模型的另一个扩展是CM可能需要其他共同因素转录活动。在最近的工作中，我们发现组蛋白脱乙酰基酶1（HDAC1）是CM/RUNX1的一部分复合物，是表达CM靶基因所必需的。使用INV（16）AML的鼠标模型，我们发现 HDAC1抑制剂肠结构抑制剂会诱导分化，并减少体内白血病燃烧。基于我们以前的工作，我们假设CM是促进基因的表达所必需的白血病维护，HDAC1是广告的重要联合因素。因此，我们建议HDAC1 抑制剂对于治疗INV（16）AML的抑制剂将特别有用。在特定目标1中，我们将使用两个定义CM在白血病维持中的作用的免费方法：一种新的敲蛋白小鼠模型允许在白血病发育后删除融合基因和诱导的shRNA敲低模型。如果CM独立细胞，我们将使用这些工具来确定CM在体内维持白血病中的作用可以引起继电器，并测试候选CM靶基因在白血病维持中的作用。具体 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，以及测试HDAC1非典型的潜在机制在转录激活中的作用。特定的目标3将测试恩替托特对治疗INV（16）AML的潜力。我们将使用遗传和患者衍生的异种移植小鼠模型来测试是否在标准治疗将减少白血病燃烧并增加生存率。我们还将测试是否使用Entinostat 抑制CM与dasatinib结合以抑制试剂盒中的合作突变比任何一个更有效独自吸毒。拟议的研究是基于我们积累的经验和我们强大的初步发现，并将解决该领域的重要差距，并对INV（16）AML患者具有直接的翻译意义。