Activating mutations in JAK2 and in MPL are present in the majority of patients with the myeloproliferative neoplasms (MPN) essential thrombocytosis (ET) and primary myelofibrosis (PMF). The identification of MPL mutations in ET and PMF demonstrates that constitutive activation of JAK2 by somatic mutations in hematopoietic cytokine receptors is an important pathogenic event in JAK2V617F-negative MPN. Expression of MPL mutations results in constitutive activation of JAK-STAT signaling and confers in vivo a myeloproliferative phenotype notable for thrombocytosis, extramedullary hematopoiesis, and myelofibrosis. Despite these important insights, the specific signaling pathways activated by different MPL and JAK2 mutations that contribute to transformation have not been determined. The reason for the relative lack of efficacy of efficacy of JAK2 inhibitors in the treatment of MPN is not understood and potential mechanisms of resistance to JAK2 inhibitors in ET and PMF have not been fully elucidated. The goals of this project are to understand how aberrant signaling leads to the development of ET and PMF and to work towards the development of novel therapies for patients with these MPN. We will analyze signaling in cell lines expressing MPL/JAK2 alleles, mouse MPN models, and primary MPN samples, and use genetic studies to assess the role and requirement for STAT3 and STAT5 signaling in ET/MF pathogenesis. We will also investigate the basis for JAK2 inhibitor resistance, and assess the requirement for JAK2 in MPL mutant mediated transformation. The long term goal of this project is to improve our understanding of the pathogenesis of ET and PMF and to work towards developing more effective therapies for patients with these MPN.

Public Health Relevance

The goal of this project is to improve our understanding of the genetic basis of myeloproliferative neoplasms, and to improve therapies for patients with these hematopoietic disorders. We will investigate the signaling pathways that contribute to these disorders through studies in mouse models and in primary patient samples. We will also work to understand the basis for resistance for current therapies for MPN patients and work to develop novel targeted therapies designed to reduce morbidity and improve survival for patients with these heretofore-incurable disorders.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151949-03
Application #
8208241
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Mufson, R Allan
Project Start
2010-07-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$432,264
Indirect Cost
$205,829
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Bhagwat, Neha; Koppikar, Priya; Keller, Matthew et al. (2014) Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. Blood 123:2075-83
Meyer, Sara C; Keller, Matthew D; Woods, Brittany A et al. (2014) Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis. Blood 124:2280-4
Rampal, Raajit; Al-Shahrour, Fatima; Abdel-Wahab, Omar et al. (2014) Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood 123:e123-33
Meyer, Sara C; Levine, Ross L (2014) Molecular pathways: molecular basis for sensitivity and resistance to JAK kinase inhibitors. Clin Cancer Res 20:2051-9
Levine, Ross L (2013) Molecular pathogenesis of AML: translating insights to the clinic. Best Pract Res Clin Haematol 26:245-8
Betts, Brian C; Abdel-Wahab, Omar; Curran, Shane A et al. (2011) Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen. Blood 118:5330-9
Liu, Fan; Zhao, Xinyang; Perna, Fabiana et al. (2011) JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell 19:283-94
Abdel-Wahab, Omar; Levine, Ross (2011) The spliceosome as an indicted conspirator in myeloid malignancies. Cancer Cell 20:420-3