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HMGA Chromatin Remodeling Proteins in Tumor Progression in Myeloproliferative Neoplasms (MPN)

HMGA 染色质重塑蛋白在骨髓增生性肿瘤 (MPN) 肿瘤进展中的作用

基本信息

批准号：
9978605
负责人：
ALISON R MOLITERNO
金额：
$ 47.78万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978605
关键词：
Acute Myelocytic Leukemia Acute leukemia Affect Automobile Driving Binding Proteins Blood Cells Blood Platelets Bone Marrow CD34 gene CSF3 gene Cell model Cells ChIP-seq Chromatin Chromatin Structure Chronic Clinical Colony-Stimulating Factor Receptors Complex Cultured Cells DNA Data Disease Disease Progression EZH2 gene Enhancers Epigenetic Process Erythrocytes Erythropoietin Receptor Evolution Gene Expression Gene Family Genes Genetic Transcription Genomics Goals Growth Factor HMGA1 gene HMGA2 gene Hematologic Neoplasms Hematology Hematopoietic Neoplasms Hematopoietic stem cells Homologous Protein Human Indolent Inflammation JAK2 gene Knock-in Lesion Leukocytes MPL gene Malignant lymphoid neoplasm Modeling Molecular Mus Mutation Myelofibrosis Myeloid Leukemia Myeloproliferative disease Oncogenes Outcome Pathway interactions Patient-Focused Outcomes Patients Pharmacology Phenotype Plasma Platelet Count measurement Play Polycythemia Vera Population Prevention strategy Production Protein Tyrosine Kinase Proteins Publishing RNA Splicing Reporting Research Risk Role Sampling Signal Transduction Solid Solid Neoplasm Staphylococcal Protein A Testing Thrombopoietin Transduction Gene Transgenic Mice Transgenic Organisms Treatment Efficacy Treatment outcome Variant Work advanced disease adverse outcome base chromatin remodeling clinical efficacy gene function genomic data histone methyltransferase in vivo innovation leukemia leukemic transformation leukemogenesis mouse model mutant novel novel therapeutic intervention overexpression pre-clinical promoter recruit self-renewal stem cells therapeutic evaluation transcription factor transcriptome sequencing tumor tumor progression

项目摘要

The goal of this proposal is to define the role of high mobility group A (HMGA) chromatin remodeling proteins in tumor progression in myeloproliferative neoplasms (MPN). MPN are a heterogeneous group of acquired, clonal hematopoietic stem and progenitor cell disorders characterized by overproduction of mature blood cells and a propensity for leukemic transformation, although the molecular mechanisms for tumor progression are unknown. Polycythemia vera (PV) is the prototypical MPN defined by acquired activating mutations in the gene encoding JAK2, the obligate tyrosine kinase of hematopoietic growth factor receptors for erythropoietin, G-CSF, and thrombopoietin, resulting in uncontrolled production of red cells, white cells, and platelets. JAK2 mutations alone, however, do not account for progression from chronic, indolent PV to acute leukemia. Importantly, outcomes for PV patients who progress to leukemia are abysmal; thus, research is needed to determine how this occurs. Our scientific premise is based on compelling preliminary data indicating that PV tumor progression is associated with overexpression in genes encoding the HMGA chromatin binding proteins. HMGA proteins modulate gene expression by remodeling chromatin and recruiting transcription factor complexes to DNA. Our group was the first to discover that HMGA genes function as potent oncogenes that drive leukemic transformation in cultured cell models and transgenic mice. Moreover, HMGA overexpression portends adverse clinical outcomes in diverse hematologic malignancies and solid tumors. In diverse tumor models, we found that HMGA1 drives tumor progression through epigenetic alterations that induce stem cell transcriptional networks. In preliminary data from ChIP-Seq in human CD34+ stem and progenitor cells, we found that HMGA1 occupies promoter-enhancer regions for genes involved in self-renewal, de- differentiation, inflammation, and myeloid leukemia. These exciting findings led us to the following hypotheses: 1) HMGA proteins are critical drivers of tumor progression in PV by inducing transcriptional networks that maintain uncontrolled self-renewal, de-differentiation, and leukemic transformation, and, 2) Targeting HMGA pathways will block tumor progression and reprogram advanced disease to a more indolent phenotype. We have >600 primary human MPN tumors with detailed clinical annotation and genomic data and we generated innovative mouse models to study HMGA in PV progression. Here, we propose to harness our unique models, tumor samples, and expertise to elucidate the role of HMGA chromatin regulators in PV progression with the following Specific Aims: 1) To determine whether HMGA overexpression predicts tumor progression and to define cooperating genomic lesions and molecular mechanisms, 2) To define the functional significance of HMGA in tumor progression in vivo using mouse models, and, 3) To investigate the clinical efficacy of targeting HMGA pathways. Our work should uncover novel mechanisms driving disease progression and open the door to new therapeutic strategies for MPN and possibly other myeloid malignancies.

本提案的目的是确定高迁移率族A（HMGA）染色质的作用骨髓增生性肿瘤（MPN）中的肿瘤进展中的重塑蛋白。MPN是一个获得性、克隆性造血干细胞和祖细胞疾病的异质组，其特征在于成熟血细胞的过度生产和白血病转化的倾向，虽然分子肿瘤进展的机制尚不清楚。真性红细胞增多症（PV）是由以下定义的原型MPN：在编码JAK 2（造血生长的专性酪氨酸激酶）的基因中获得性激活突变促红细胞生成素、G-CSF和促血小板生成素的因子受体，导致红细胞的不受控制的产生，白色细胞和血小板。然而，JAK 2突变本身并不能解释从慢性、惰性、 PV到急性白血病。重要的是，进展为白血病的PV患者的结局非常糟糕;因此，需要进行研究以确定这是如何发生的。我们的科学前提是基于令人信服的初步数据表明PV肿瘤进展与编码HMGA染色质的基因的过表达相关结合蛋白HMGA蛋白通过重塑染色质和募集来调节基因表达转录因子与DNA的复合物。我们的研究小组是第一个发现HMGA基因的功能是有效的，在培养的细胞模型和转基因小鼠中驱动白血病转化的癌基因。此外，HMGA 过表达预示着多种血液恶性肿瘤和实体瘤的不良临床结果。在在不同的肿瘤模型中，我们发现HMGA 1通过表观遗传改变驱动肿瘤进展，干细胞转录网络在人CD 34+干细胞和祖细胞中ChIP-Seq的初步数据中，细胞中，我们发现HMGA 1占据了参与自我更新、去甲肾上腺素（DEG）分化、炎症和髓性白血病。这些令人兴奋的发现使我们得出以下假设： 1)HMGA蛋白通过诱导转录网络，维持不受控制的自我更新、去分化和白血病转化，以及，2）靶向HMGA 通路将阻断肿瘤进展并将晚期疾病重新编程为更惰性的表型。我们我们拥有超过600种原发性人类MPN肿瘤，并附有详细的临床注释和基因组数据，我们生成了创新的小鼠模型，研究HMGA在PV进展中的作用。在这里，我们建议利用我们独特的模型，肿瘤样本，以及阐明HMGA染色质调节剂在PV进展中的作用的专业知识，以下具体目的：1）确定HMGA过表达是否预测肿瘤进展，确定协同的基因组病变和分子机制，2）确定 HMGA在体内肿瘤进展中使用小鼠模型，以及，3）研究靶向HMGA的临床疗效。 HMGA途径。我们的工作应该揭示驱动疾病进展的新机制，为MPN和可能的其他骨髓恶性肿瘤的新治疗策略打开了大门。