Aberrant megakaryopoiesis in the myeloproliferative neoplasms.

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PROJECT SUMMARY Primary myelofibrosis (PMF) is characterized by myeloproliferation, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleen of patients are full of atypical megakaryocytes that contribute to fibrosis through the release of cytokines including TGF-β. Our overarching hypothesis is that abnormal megakaryocytes are key drivers of not only bone marrow fibrosis, but also other phenotypes of primary myelofibrosis, and that targeting them will ameliorate the disease. In the first funding period, we identified small molecules that induce maturation and polyploidization of malignant megakaryocytes in mouse models of PMF as well as primary human patient specimens. Based on this NHLBI- funded research, we have opened a Phase 1 trial of one of these megakaryocyte polyploidization agents, Alisertib, in PMF. In this competing renewal, we will probe the molecular nature of the defects in PMF megakaryocytes, and also determine their necessity and sufficiency in the disease. Our preliminary data show that expression of the key transcription factor GATA1 is suppressed in the majority of both human and mouse PMF megakaryocytes and further suggest that this deficiency is due to impaired ribosome function. We also present the surprising result that expression of JAK2V617F selectively in megakaryocytes is sufficient to cause polycythemia in vivo. In Aim 1, we will investigate the link between activated JAK/STAT signaling, GATA1, and ribosome function. In Aim 2 we will study how megakaryocyte expression of JAK2 influences the growth of other cells and also determine whether megakaryocytes are essential for the disease. This work is innovative in that we are the first to reveal that there is defect in ribosomes in a megakaryocytic disorder and that megakaryocyte-selective expression of JAK2V617F leads not only to enhanced megakaryopoiesis, but also to polycythemia in a cell non-autonomous manner. Our research is significant in that it will shed new light on megakaryocyte biology and pathogenesis and may aid in the identification of additional new potential therapies for the MPNs. In addition, our work is also relevant to Diamond Blackfan Anemia, as GATA1 mutations account for a subset of cases and there appears to be a relationship between ribosomal gene mutations and GATA1 translation. Finally, our research will provide additional insights to support the development of agents that selectively target megakaryocytes in this disease.