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

作者：Kaufmann Kai B; Gruender Albert; Hadlich Tobias; Wehrle Julius; Gothwal Monika; Bogeska Ruzhica; Seeger Thalia S; Kayser Sarah; Pham Kien Binh; Jutzi Jonas S; Ganzenmueller Lucas; Steinemann Doris; Schlegelberger Brigitte; Wagner Julia M; Jung Manfred; Will Britta; Steidl Ulrich; Aumann Konrad; Werner Martin; Guenther Thomas; Schuele Roland; Rambaldi Alessandro; Pahl Heike L^*

来源：Journal of Experimental Medicine, 2012, 209(1): 35-50.

DOI：10.1084/jem.20110540

The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often over-expressed 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.

• 出版日期2012-1-16