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.
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.
|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|
Showing the most recent 10 out of 195 publications