Molecular Pathogenesis and Therapy of ET and PMF

摘要 骨髓增生性肿瘤（MPN）患者真性红细胞增多症（PV）， 原发性血小板增多症（ET）和原发性骨髓纤维化（PMF） 血细胞减少、骨髓纤维化和/或转化为急性白血病。的 在大多数人中鉴定JAK-STAT途径中的体细胞激活突变， MPN患者导致JAK激酶抑制剂的临床开发。虽然他们 提供重要的临床益处，目前的JAK抑制剂未显示疾病改善 在大多数患者中。此外，最近的研究表明， 染色质修饰剂ASXL 1与PMF的不良临床结局相关。这些 数据强调需要新的治疗方法，MF患者的基础上， 对疾病发病机理的机械见解。我们建议调查 JAK 2和ASXL 1突变协同诱导骨髓细胞增殖的机制 转化，并研究MF的新治疗方法。这将包括 评价JAK-STAT通路和ASXL 1并行影响的研究 突变对MPN发病机制、进展和对靶向 治疗我们还将研究新的治疗方法的作用，特别是 II型JAK 2抑制剂和靶向JAK 2和 MF鼠模型和主要患者样品中的LSD 1/BRD 4。这方面的研究 该项目将利用新的，遗传上准确的小鼠模型， 对来自MPN-RC样本库的原始样本进行研究。最重要的是 该项目的研究旨在证明新的治疗方法， 然后转移到临床进行基于近期机制的临床试验。

ABSTRACT Patients with the myeloproliferative neoplasms (MPNs) Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) suffer progressive cytopenias, bone marrow fibrosis and/or transformation to acute leukemia. The identification of somatic activating mutations in the JAK-STAT pathway in the majority of MPN patients led to the clinical development of JAK kinase inhibitors. Although they provide important clinical benefit, current JAK inhibitors do not show disease-modifying activity in most patients. In addition, recent studies have shown that mutations in the chromatin modifier ASXL1 are associated with adverse clinical outcome in PMF. These data underscore the need novel therapeutic approaches for MF patients based on mechanistic insight into disease pathogenesis. We propose to investigate the mechanisms by which JAK2 and ASXL1 mutations cooperate to induce myeloid transformation, and to investigate novel therapeutic approaches in MF. This will include studies which evaluate the impact of concurrent JAK-STAT pathway and ASXL1 mutations on MPN pathogenesis, progression and therapeutic resistance to targeted therapies. We will also investigate the role of novel therapeutic approaches, specifically type II JAK2 inhibitors and combined signaling/epigenetic therapies targeting JAK2 and LSD1/BRD4 in MF murine models and primary patient samples. The studies in this project will leverage novel, genetically accurate murine models coupled with detailed studies of primary samples from the MPN-RC sample bank. Most importantly, the studies in this project are aimed to credential novel therapeutic approaches which can then be transitioned to the clinic for near-term mechanism based clinical trials.