A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2

• Published in: The Journal of experimental medicine Vol. 209; no. 1; pp. 35 - 50
• Main Authors: Kaufmann, Kai B, Gründer, Albert, Hadlich, Tobias, Wehrle, Julius, Gothwal, Monika, Bogeska, Ruzhica, Seeger, Thalia S, Kayser, Sarah, Pham, Kien-Binh, Jutzi, Jonas S, Ganzenmüller, Lucas, Steinemann, Doris, Schlegelberger, Brigitte, Wagner, Julia M, Jung, Manfred, Will, Britta, Steidl, Ulrich, Aumann, Konrad, Werner, Martin, Günther, Thomas, Schüle, Roland, Rambaldi, Alessandro, Pahl, Heike L
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 16.01.2012
• Subjects: Animals; Blood Cell Count; Blood Cells - metabolism; Cell Differentiation - genetics; Chromatin - metabolism; Disease Models, Animal; Disease Progression; Gene Expression; Gene Expression Regulation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Humans; Leukemia - metabolism; Leukemia - pathology; Mice; Mice, Transgenic; Myeloproliferative Disorders - drug therapy; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - metabolism; NF-E2 Transcription Factor - genetics; Phenotype
• DOI: 10.1084/jem.20110540
• ISSN: 0022-1007

The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase inhibitor (HDAC-I) vorinostat restored physiological levels of histone H3 acetylation, decreased NF-E2 expression, and normalized platelet numbers. Similarly, MPN patients treated with an HDAC-I exhibited a decrease in NF-E2 expression. These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies.