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

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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. © 2012 Kaufmann et al.

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Kaufmann, K. B., Gründer, A., Hadlich, T., Wehrle, J., Gothwal, M., Bogeska, R., … 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

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