Molecular Pathogenesis and Therapy of ET and PMF

描述（由申请方提供）：JAK 2和MPL中的激活突变存在于大多数骨髓增生性肿瘤（MPN）、原发性血小板增多（ET）和原发性骨髓纤维化（PMF）患者中。ET和PMF中MPL突变的鉴定表明，由造血细胞因子受体中的体细胞突变引起的JAK 2的组成性激活是JAK 2 V617 F阴性MPN中的重要致病事件。MPL突变的表达导致JAK-STAT信号传导的组成性激活，并在体内赋予以血小板增多、髓外造血和骨髓纤维化为特征的骨髓增殖表型。尽管有这些重要的见解，但尚未确定由不同MPL和JAK 2突变激活的有助于转化的特定信号传导途径。JAK 2抑制剂治疗MPN疗效相对缺乏的原因尚不清楚，ET和PMF中JAK 2抑制剂耐药的潜在机制尚未完全阐明。该项目的目标是了解异常信号传导如何导致ET和PMF的发展，并致力于为这些MPN患者开发新的治疗方法。我们将分析表达MPL/JAK 2等位基因的细胞系、小鼠MPN模型和原发性MPN样本中的信号传导，并使用遗传学研究评估STAT 3和STAT 5信号传导在ET/MF发病机制中的作用和要求。我们还将研究JAK 2抑制剂抗性的基础，并评估MPL突变体介导的转化中对JAK 2的需求。该项目的长期目标是提高我们对ET和PMF发病机制的理解，并致力于为这些MPN患者开发更有效的治疗方法。 公共卫生相关性： 该项目的目标是提高我们对骨髓增生性肿瘤遗传基础的理解，并改善这些造血系统疾病患者的治疗。我们将通过对小鼠模型和原发性患者样本的研究，调查导致这些疾病的信号通路。我们还将努力了解MPN患者当前治疗的耐药性基础，并努力开发新的靶向治疗，旨在降低这些迄今无法治愈的疾病患者的发病率并提高其生存率。

DESCRIPTION (provided by applicant): Activating mutations in JAK2 and in MPL are present in the majority of patients with the myeloproliferative neoplasms (MPN) essential thrombocytosis (ET) and primary myelofibrosis (PMF). The identification of MPL mutations in ET and PMF demonstrates that constitutive activation of JAK2 by somatic mutations in hematopoietic cytokine receptors is an important pathogenic event in JAK2V617F-negative MPN. Expression of MPL mutations results in constitutive activation of JAK-STAT signaling and confers in vivo a myeloproliferative phenotype notable for thrombocytosis, extramedullary hematopoiesis, and myelofibrosis. Despite these important insights, the specific signaling pathways activated by different MPL and JAK2 mutations that contribute to transformation have not been determined. The reason for the relative lack of efficacy of efficacy of JAK2 inhibitors in the treatment of MPN is not understood and potential mechanisms of resistance to JAK2 inhibitors in ET and PMF have not been fully elucidated. The goals of this project are to understand how aberrant signaling leads to the development of ET and PMF and to work towards the development of novel therapies for patients with these MPN. We will analyze signaling in cell lines expressing MPL/JAK2 alleles, mouse MPN models, and primary MPN samples, and use genetic studies to assess the role and requirement for STAT3 and STAT5 signaling in ET/MF pathogenesis. We will also investigate the basis for JAK2 inhibitor resistance, and assess the requirement for JAK2 in MPL mutant mediated transformation. The long term goal of this project is to improve our understanding of the pathogenesis of ET and PMF and to work towards developing more effective therapies for patients with these MPN. PUBLIC HEALTH RELEVANCE: The goal of this project is to improve our understanding of the genetic basis of myeloproliferative neoplasms, and to improve therapies for patients with these hematopoietic disorders. We will investigate the signaling pathways that contribute to these disorders through studies in mouse models and in primary patient samples. We will also work to understand the basis for resistance for current therapies for MPN patients and work to develop novel targeted therapies designed to reduce morbidity and improve survival for patients with these heretofore-incurable disorders.