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 #
5P01CA108671-12
Application #
9884553
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
12
Fiscal Year
2020
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
Migliaccio, Anna Rita; Varricchio, Lilian (2018) Concise Review: Advanced Cell Culture Models for Diamond Blackfan Anemia and Other Erythroid Disorders. Stem Cells 36:172-179
Ling, Te; Crispino, John D; Zingariello, Maria et al. (2018) GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy. Expert Rev Hematol 11:169-184
Migliaccio, Anna Rita; Uversky, Vladimir N (2018) Dissecting physical structure of calreticulin, an intrinsically disordered Ca2+-buffering chaperone from endoplasmic reticulum. J Biomol Struct Dyn 36:1617-1636
Peeken, Jan C; Jutzi, Jonas S; Wehrle, Julius et al. (2018) Epigenetic regulation of NFE2 overexpression in myeloproliferative neoplasms. Blood 131:2065-2073
Wang, Xiaoli; Hu, Cing Siang; Petersen, Bruce et al. (2018) Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells. Blood Adv 2:2378-2388
Zimran, Eran; Tripodi, Joseph; Rampal, Raajit et al. (2018) Genomic characterization of spleens in patients with myelofibrosis. Haematologica 103:e446-e449
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 33:785-787
Qiu, Jiajing; Salama, Mohamed E; Hu, Cing Siang et al. (2018) The characteristics of vessel lining cells in normal spleens and their role in the pathobiology of myelofibrosis. Blood Adv 2:1130-1145
Pronier, Elodie; Cifani, Paolo; Merlinsky, Tiffany R et al. (2018) Targeting the CALR interactome in myeloproliferative neoplasms. JCI Insight 3:
Migliaccio, Anna Rita (2018) A vicious interplay between genetic and environmental insults in the etiology of blood cancers. Exp Hematol 59:9-13

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