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

这项建议的目标是确定高迁移率A组(HMGA)染色质的作用 骨髓增生性肿瘤(MPN)中肿瘤进展中的重塑蛋白。MPN是 一组获得性、克隆性造血干/祖细胞疾病，其特征是 成熟血细胞的过度生产和白血病转化的倾向，尽管分子 肿瘤进展的机制尚不清楚。真性红细胞增多症(PV)是由 获得编码JAK2基因的激活突变，JAK2是造血生长的专有酪氨酸酶 促红细胞生成素、粒细胞集落刺激因子和血小板生成素的因子受体，导致红细胞的不受控制的产生， 白血球和血小板。然而，JAK2基因突变本身并不能解释慢性惰性疾病的进展 从PV到急性白血病。重要的是，进展为白血病的PV患者的结局是糟糕的；因此， 需要研究来确定这种情况是如何发生的。我们的科学前提是基于令人信服的初步数据 提示PV肿瘤进展与HMGA染色质编码基因的过度表达有关 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形成复合体。我们小组是第一个发现HMGA基因功能的人 在培养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 在不同的血液系统恶性肿瘤和实体瘤中，过度表达预示着不良的临床结果。在……里面 不同的肿瘤模型，我们发现HMGA1通过表观遗传改变促进肿瘤进展 干细胞转录网络。人CD34+干祖细胞CHIP-SEQ的初步数据 细胞中，我们发现HMGA1占据了参与自我更新、去激活基因的启动子-增强子区域。 分化、炎症和髓系白血病。这些令人兴奋的发现让我们得出了以下假设： 1)HMGA蛋白通过诱导转录网络而成为PV中肿瘤进展的关键驱动因素 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 通路将阻止肿瘤的进展，并将晚期疾病重新编程为更懒惰的表型。我们 具有详细的临床注释和基因组数据的600个原发人类MPN肿瘤，我们生成了 研究HMGA在PV进展中的创新小鼠模型。在这里，我们建议利用我们独特的模型， 肿瘤样本和专业知识，以阐明HMGA染色质调节剂在PV进展中的作用 以下具体目标：1)确定HMGA过表达是否预测肿瘤进展和 定义协同基因组损伤和分子机制，2)定义功能意义 HMGA在小鼠体内肿瘤进展中的作用，以及，3)研究靶向治疗的临床疗效 HMGA途径。我们的工作应该揭示推动疾病进展和开放的新机制 为治疗MPN和可能的其他髓系恶性肿瘤开辟新的治疗策略之门。

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.