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-?. 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.
Primary myelofibrosis (PMF), one of the subtypes of the myeloproliferative neoplasms, is a disease that is characterized by the expansion of atypical megakaryocytes which make significant contributions to disease pathogenesis. Here we will investigate the nature of the defects in this lineage with the goal of better understanding the disease. Our work will also provide important clues to aid in the development of novel approaches to normalize hematopoiesis and improve the outcome of PMF patients.
|Zhao, Baobing; Mei, Yang; Cao, Lan et al. (2018) Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms. J Clin Invest 128:125-140|
|Suraneni, Praveen K; Corey, Seth J; Hession, Michael J et al. (2018) Dynamins 2 and 3 control the migration of human megakaryocytes by regulating CXCR4 surface expression and ITGB1 activity. Blood Adv 2:3540-3552|
|Payton, Marc; Cheung, Hung-Kam; Ninniri, Maria Stefania S et al. (2018) Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes. Mol Cancer Ther 17:2575-2585|
|Fu, Chunling; Wen, Qiang Jeremy; Marinaccio, Christian et al. (2018) AKT activation is a feature of CALR mutant myeloproliferative neoplasms. Leukemia :|
|Gilles, Laure; Arslan, Ahmet Dirim; Marinaccio, Christian et al. (2017) Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis. J Clin Invest 127:1316-1320|
|Wen, Qiang Jeremy; Yang, Qiong; Goldenson, Benjamin et al. (2015) Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. Nat Med 21:1473-80|
|Goldenson, Benjamin; Kirsammer, Gina; Stankiewicz, Monika J et al. (2015) Aurora kinase A is required for hematopoiesis but is dispensable for murine megakaryocyte endomitosis and differentiation. Blood 125:2141-50|
|Goldenson, B; Crispino, J D (2015) The aurora kinases in cell cycle and leukemia. Oncogene 34:537-45|
|Krause, Diane S; Crispino, John D (2013) Molecular pathways: induction of polyploidy as a novel differentiation therapy for leukemia. Clin Cancer Res 19:6084-8|