Aberrant Megakaryopoiesis in the Myeloproliferative Neoplasms

描述（由申请人提供）：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）的一个特征。在正常情况下，固定的巨核细胞祖细胞在有限范围内增殖，然后产生少量分化和多倍体巨核细胞。然而，在关键信号分子（如MPL或JAK2）获得突变后，巨核细胞祖细胞扩增并导致ET中的血小板增多或PMF中的骨髓纤维化。导致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，我们将确定PMF巨核细胞中失调的转录途径，并描述与ET巨核细胞相比异常巨核生成的原因。我们还将确定巨核细胞分化和多倍体化的小分子诱导剂是否能有效抑制mpn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体化的机制。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，而这一程序可以用巨核细胞多倍体和分化的小分子诱导剂逆转。这项工作是创新的，因为我们是第一个在分子水平上全面描述PMF和正常巨核细胞之间差异的人。此外，我们正在使用创新的小分子来推进我们对mpn的理解，并开发新的靶向治疗方法。我们的工作意义重大，因为临床试验中没有一种JAK2抑制剂能改善患者的骨髓纤维化：我们的研究旨在确定这种使人衰弱的疾病的根本原因，这将有助于开发新的治疗方法。

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.