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 EZH2 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 in this research consortium.

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 in this research consortium.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA108671-10A1
Application #
9416772
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Varricchio, Lilian; Falchi, Mario; Dall'Ora, Massimiliano et al. (2017) Calreticulin: Challenges Posed by the Intrinsically Disordered Nature of Calreticulin to the Study of Its Function. Front Cell Dev Biol 5:96
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