Patients with the myeloproliferative neoplasms (MPNs) Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) suffer progressive cytopenias, bone marrow fibrosis and/or transformation to acute leukemia. The identification of somatic activating mutations in the JAK-STAT pathway in the majority of MPN patients led to the clinical development of JAK kinase inhibitors. Although they provide important clinical benefit, current JAK inhibitors do not show disease-modifying activity in most patients. In addition, recent studies have shown that mutations in the chromatin modifier ASXL1 are associated with adverse clinical outcome in PMF. These data underscore the need novel therapeutic approaches for MF patients based on mechanistic insight into disease pathogenesis. We propose to investigate the mechanisms by which JAK2 and ASXL1 mutations cooperate to induce myeloid transformation, and to investigate novel therapeutic approaches in MF. This will include studies which evaluate the impact of concurrent JAK-STAT pathway and ASXL1 mutations on MPN pathogenesis, progression and therapeutic resistance to targeted therapies. We will also investigate the role of novel therapeutic approaches, specifically type II JAK2 inhibitors and combined signaling/epigenetic therapies targeting JAK2 and LSD1/BRD4 in MF murine models and primary patient samples. The studies in this project will leverage novel, genetically accurate murine models coupled with detailed studies of primary samples from the MPN-RC sample bank. Most importantly, the studies in this project are aimed to credential novel therapeutic approaches which can then be transitioned to the clinic for near-term mechanism based clinical trials.

Public Health Relevance

There is a need for new treatments for myelofibrosis (MF) patients based on laboratory insight into disease pathogenesis. We will use studies of murine models of MF and primary patient samples to understand how different genetic mutations contribute to MF development and to test novel treatment approaches. Most importantly, the studies in this project are aimed to validate novel therapies that can then be rapidly tested in clinical trials.

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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Forry, Suzanne L
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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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