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.

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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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Mufson, R Allan
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Sloan-Kettering Institute for Cancer Research
New York
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Kleppe, Maria; Koche, Richard; Zou, Lihua et al. (2018) Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell 33:29-43.e7
Verstovsek, Srdan; Manshouri, Taghi; Pilling, Darrell et al. (2016) Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis. J Exp Med 213:1723-40
Meyer, Sara C; Keller, Matthew D; Chiu, Sophia et al. (2015) CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms. Cancer Cell 28:15-28
Kleppe, Maria; Kwak, Minsuk; Koppikar, Priya et al. (2015) JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov 5:316-31
Kleppe, Maria; Comen, Elizabeth; Wen, Hannah Y et al. (2015) Somatic mutations in leukocytes infiltrating primary breast cancers. NPJ Breast Cancer 1:15005
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
Viny, Aaron D; Levine, Ross L (2014) Genetics of myeloproliferative neoplasms. Cancer J 20:61-5
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
Rampal, Raajit; Ahn, Jihae; Abdel-Wahab, Omar et al. (2014) Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A 111:E5401-10
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

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