The myeloproliferative neoplasms (MPN), originate at the level of the pluripotent hematopoietic stem cell. Each MPN can undergo clonal evolution and hematologic progression that terminates in bone marrow failure, marked by progressive man'ow fibrosis, extramedullary hematopoiesis, and/or transfonnation to acute leultemia (AL). The leading causes of morbidity and mortality in PV and ET are thrombotic complications, followed by myelofibrosis and AL. PMF has a much graver prognosis due to marrow failure, the development of massive hepato-splenomegaly and a higher rate of transformation to AL. The somatic mutation JAK2 V617F, present in between 30-95% of patients with MPN, confers constitutive tyrosine kinase activity and plays a role in the pathophysiology of MPN. MPN have not been the subject of an organized group of investigators focused on studying their pathophysiology in a manner which would lead to the development of translational clinical trials since the demise of the P Vera Study Group two decades ago. Although individual investigators have conducted clinical trials and two multi-institutional phase III studies have been completed establishing the efficacy of aspirin in reducing risk of thrombosis, and the utility of hydroxyurea in the long term in patients with ET none of these treatments has changed the natural history of the MPN. We have established the Myeloproliferative Disorders Research Consortium (MPD-RC) an intemationai group of 24 academic centers in the US and Europe to conduct translational clinical trials in MPN. The goals of this project are to conduct a series of hypothesis driven MPD-RC investigator initiated translational clinical trials, based on interactions with the laboratory based projects in the MPD-RC, in order to identify active new agents and approaches that alone or in combination, can change both the treatment paradigm and natural history of the MPN leading to improved outcomes for such patients.
The specific aims i nclude plans to conduct phase l/ll trials in patients with PMF testing such novel approaches as: CEP 701, a JAK2 inhibitor;azacitidine and vorinostat an epigenetic approach to disease modification based on observations made in Project 5: plitidepsin an inhibitor of protein tyrosine phosphatases known to change the natural history of MF in a Gata(low)'mouse model developed in project 4, and allogeneic stem cell transplant as a potential curative approach. In PV, the effects of pegylated interferon alpha-2a as well as anti-thrombotic agents will be studied in high risk PV and ET in phase 2/3 trials. These investigator initiated trials are completely dependent on the clinical research infrastructure of the MPD-RC

Public Health Relevance

The overall goal of this project is to employ the complementary skills and efforts of the scientifically diverse membership of the MPD-RC to generate the foundation with which to develop novel therapeutic strategies for the treatment of patients with MPN. Such therapies will be evaluated in rigorous, well constructed investigator initiated clinical trials to be perfonned and analyzed independently by the member institution of the MPD-RC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-J (O1))
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Icahn School of Medicine at Mount Sinai
New York
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Gupta, Vikas; Kosiorek, Heidi E; Mead, Adam et al. (2018) Ruxolitinib Therapy Followed by Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation for Myelofibrosis: Myeloproliferative Disorders Research Consortium 114 Study. Biol Blood Marrow Transplant :
Gnanapragasam, Merlin Nithya; Crispino, John D; Ali, Abdullah M et al. (2018) Survey and evaluation of mutations in the human KLF1 transcription unit. Sci Rep 8:6587
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

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