Aberrant Megakaryopoiesis in the Myeloproliferative Neoplasms

描述(申请人提供)：巨核细胞发育的异常调节是原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)的特征。在正常条件下，承诺的巨核细胞前体细胞有限地增殖，然后产生少量分化的多倍体巨核细胞。然而，一旦获得了关键信号分子的突变，如MPL或JAK2，巨核系祖细胞就会扩张，并导致ET的血小板增多或PMF的骨髓纤维化。导致这两种疾病巨核细胞表型极端差异的具体分子变化和机制尚不清楚。在这个项目中，我们将识别PMF巨核细胞中异常调控的转录途径，并与ET巨核细胞相比，鉴定异常巨核细胞生成的原因。我们还将确定巨核细胞分化和多倍化的小分子诱导剂是否有效地抑制MPNS中异常巨核细胞的增殖。最后，我们将研究这些化合物导致异常巨核细胞分化和多倍化的机制。我们的总体假设是PMF中的巨核细胞是异常的，因为它们异常地表达髓系转录因子，并且这种程序可以被巨核细胞多倍化和分化的小分子诱导剂逆转。这项工作的创新之处在于，我们首次在分子水平上全面描述了PMF与正常巨核细胞之间的差异。此外，我们正在使用创新的小分子来促进我们对MPNS的理解，并开发新的靶向疗法。我们的工作具有重要意义，因为临床试验中的JAK2抑制剂都没有改善患者的骨髓纤维化：我们旨在确定这种衰弱疾病的根本原因的研究将有助于新疗法的开发。

DESCRIPTION (provided by applicant): Aberrant regulation of megakaryocyte development is a feature of both essential thrombocythemia (ET) and primary myelofibrosis (PMF). Under normal conditions, committed megakaryocyte progenitors proliferate to a limited extent and then give rise to small numbers of differentiated and polyploid megakaryocytes. However, upon acquisition of mutations in key signaling molecules, such as MPL or JAK2, megakaryocyte progenitors expand and lead to thrombocytosis in ET or myelofibrosis in PMF. The specific molecular changes and mechanisms responsible for the extreme differences in the megakaryocyte phenotype of the two disorders are unknown. In this project, we will identify transcriptional pathways that are dysregulated in PMF megakaryocytes and characterize the causes of aberrant megakaryopoiesis as compared to ET megakaryocytes. We will also determine whether small molecule inducers of megakaryocyte differentiation and polyploidization are effective at restraining the proliferation of aberrant megakaryocytes in MPNs. Finally, we will study the mechanism by which these compounds lead to differentiation and polyploidization of abnormal megakaryocytes. Our overall hypothesis is that megakaryocytes in PMF are abnormal because they aberrantly express myeloid transcription factors and that this program can be reversed with small molecule inducers of megakaryocyte polyploidization and differentiation. This work is innovative in that we are the first to comprehensively describe the differences between PMF and normal megakaryocytes at the molecular level. Moreover, we are using innovative small molecules to advance our understanding of MPNs and to develop new targeted therapies. Our work is significant in that none of the JAK2 inhibitors in clinical trials ameliorate bone marrow myelofibrosis in patients: our research aimed at identifying the root cause of this debilitating condition will aid in development of new therapies.