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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA108671-08
Application #
8722847
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
$304,900
Indirect Cost
$209,635
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Wang, Xiaoli; Haylock, David; Hu, Cing Siang et al. (2016) A thrombopoietin receptor antagonist is capable of depleting myelofibrosis hematopoietic stem and progenitor cells. Blood 127:3398-409
Divoky, Vladimir; Song, Jihyun; Horvathova, Monika et al. (2016) Delayed hemoglobin switching and perinatal neocytolysis in mice with gain-of-function erythropoietin receptor. J Mol Med (Berl) 94:597-608
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
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
Lu, Min; Xia, Lijuan; Liu, Yen-Chun et al. (2015) Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells. Blood 126:972-82
Wang, Xiaoli; Cho, Sool Yeon; Hu, Cing Siang et al. (2015) C-X-C motif chemokine 12 influences the development of extramedullary hematopoiesis in the spleens of myelofibrosis patients. Exp Hematol 43:100-9.e1
Kovacsovics-Bankowski, Magdalena; Kelley, Todd W; Efimova, Olga et al. (2015) Changes in peripheral blood lymphocytes in polycythemia vera and essential thrombocythemia patients treated with pegylated-interferon alpha and correlation with JAK2(V617F) allelic burden. Exp Hematol Oncol 5:28
Swierczek, S; Lima, L T; Tashi, T et al. (2015) Presence of polyclonal hematopoiesis in females with Ph-negative myeloproliferative neoplasms. Leukemia 29:2432-4
Funnell, Alister P W; Prontera, Paolo; Ottaviani, Valentina et al. (2015) 2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment. Blood 126:89-93
Falchi, Mario; Varricchio, Lilian; Martelli, Fabrizio et al. (2015) Dexamethasone targeted directly to macrophages induces macrophage niches that promote erythroid expansion. Haematologica 100:178-87

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