Despite recent advances in our understanding of the development of Myeloproliferative Neoplasms (MPNs), the pathophysiology of these disorders remains poorly understood. Especially the predisposition of MPN patients to transform to acute leukemia is not elucidated. Based on our observation that the transcription factor nuclear factor erythroid 2 (NF-E2) is overexpressed in the majority of MPN patients, we have established a murine model for MPNs, by overexpressing NF-E2 in vivo. Besides the JAK2 V617F and c-MpI W515X mouse models, this is the only murine model of MPN that employs a molecular aberration observed in MPN patients. NF-E2 was overexpressed in all hematopoietic lineages including hematopoietic progenitor cells. Two independently generated founder lines show a phenotype with many features of MPNsj including thrombocytosis, splenomegaly and MPN-like changes in bone marrow (BM) histology. The number of BM erythroid, myeloid and megakaryocytic precursors are significantly increased in NF-E2 transgenic (tg) mice, notably the number of autonomous, EPO-independent erythroid colonies. EPO-independent colonies are a pathognomonic hallmark of MPN patients. NF-E2 transgenic mice display significantly increased mortality with autopsy findings resembling those of MPN patients including splanchnic thrombosis and bleeding diatheses. At 20 months of age, one mouse (7.6%) developed acute leukemia. Our murine model therefore displays a phenotype closely resembling many features of MPN. In addition, our preliminary data indicate that NF-E2 overexpression may predispose to the development of acute leukemia. Based on this data, we formulate the following hypotheses: Hypothesis 1: NF-E2 overexpression alters hematopoietic stem cells (HSCs) resulting in the development of an MPN phenotype. NF-E2 overexpression causes cellautonomous changes in HSCs, the phenotype is therefore transplantable and constitutes a hematopoietic stem cell disorder.
Specific Aim 1 : To perform primary and secondary transplants and to characterize the stem cell compartment of NF-E2 transgenic donor and recipient mice. Hypothesis 2: NF-E2 overexpression constitutes a pre-leukemic state and predisposes to the evolution to acute leukemia.
Specific Aim 2 : To treat NF-E2 transgenic and control mice with the mutagen N-ethyl-N-nitrosourea ENU and observe the frequency of leukemic transformation. Hypothesis 3: The pathophysiological changes evoked by NF-E2 overexpression are treatable by pharmacologic intervention.
Specific Aim 3 : To treat NF-E2 transgenic mice with pharmacological agents currently in pre-clinical or phase I clinical trials for MPN patients.

Public Health Relevance

This project will establish the role of the protein NF-E2 in the pathophysiology of MPNs and their predisposition to leukemic evolution. The data generated will demonstrate whether antagonizing the effect of NF-E2 overexpression reduces the risk of leukemic transformation. If beneficial effects are shown, agents antagonizing NF-E2 effects will be examined in phase-l trials in MPN patients. These data are expected to reveal novel therapeutic strategies for the treatment of patients with MPN.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
New York
United States
Zip Code
Gilles, Laure; Arslan, Ahmet Dirim; Marinaccio, Christian et al. (2017) Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis. J Clin Invest 127:1316-1320
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
Zingariello, M; Sancillo, L; Martelli, F et al. (2017) The thrombopoietin/MPL axis is activated in the Gata1(low) mouse model of myelofibrosis and is associated with a defective RPS14 signature. Blood Cancer J 7:e572
Falchi, Mario; Varricchio, Lilian; Martelli, Fabrizio et al. (2017) The Calreticulin control of human stress erythropoiesis is impaired by JAK2V617F in polycythemia vera. Exp Hematol 50:53-76
Lanikova, Lucie; Reading, N Scott; Hu, Hao et al. (2017) Evolutionary selected Tibetan variants of HIF pathway and risk of lung cancer. Oncotarget 8:11739-11747
Sergueeva, Adelina; Miasnikova, Galina; Shah, Binal N et al. (2017) Prospective study of thrombosis and thrombospondin-1 expression in Chuvash polycythemia. Haematologica 102:e166-e169
Wang, Linghua; Wheeler, David A; Prchal, Josef T (2016) Acquired uniparental disomy of chromosome 9p in hematologic malignancies. Exp Hematol 44:644-52
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Migliaccio, Anna Rita (2016) To condition or not to condition-That is the question: The evolution of nonmyeloablative conditions for transplantation. Exp Hematol 44:706-12
Spangrude, Gerald J; Lewandowski, Daniel; Martelli, Fabrizio et al. (2016) P-Selectin Sustains Extramedullary Hematopoiesis in the Gata1 low Model of Myelofibrosis. Stem Cells 34:67-82

Showing the most recent 10 out of 181 publications