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

Kai B. Kaufmann, Albert Gründer, Tobias Hadlich, Julius Wehrle, Monika Gothwal, Ruzhica Bogeska, Thalia S. Seeger, Sarah Kayser, Kien Binh Pham, Jonas S. Jutzi, Lucas Ganzenmüller, Doris Steinemann, Brigitte Schlegelberger, Julia M. Wagner, Manfred Jung, Britta Will, Ulrich Steidl, Konrad Aumann, Martin Werner, Thomas GüntherRoland Schüle, Alessandro Rambaldi, Heike L. Pahl

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)35-50
Number of pages16
JournalJournal of Experimental Medicine
Volume209
Issue number1
DOIs
StatePublished - Jan 1 2012

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Kaufmann, K. B., Gründer, A., Hadlich, T., Wehrle, J., Gothwal, M., Bogeska, R., Seeger, T. S., Kayser, S., Pham, K. B., Jutzi, J. S., Ganzenmüller, L., Steinemann, D., Schlegelberger, B., Wagner, J. M., Jung, M., Will, B., Steidl, U., Aumann, K., Werner, M., ... Pahl, H. L. (2012). A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2. Journal of Experimental Medicine, 209(1), 35-50. https://doi.org/10.1084/jem.20110540