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 aim ed at identifying the root cause of this debilitating condition will aid in development of new therapies.

Public Health Relevance

Ongoing clinical trials demonstrate that although JAK inhibitors offer symptomatic relief for patients with MPNs, they are not curative. Here we will investigate the nature of the defects of the megakaryocyte lineage within MPN patients. Our research will provide important clues to assist in development of novel approaches to normalize thrombopoiesis and myelofibrosis in MPNs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
4R01HL112792-04
Application #
9059160
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
El Kassar, Nahed
Project Start
2013-08-01
Project End
2017-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Fu, Chunling; Wen, Qiang Jeremy; Marinaccio, Christian et al. (2018) AKT activation is a feature of CALR mutant myeloproliferative neoplasms. Leukemia :
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
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