TY - JOUR
T1 - A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2
AU - Kaufmann, Kai B.
AU - Gründer, Albert
AU - Hadlich, Tobias
AU - Wehrle, Julius
AU - Gothwal, Monika
AU - Bogeska, Ruzhica
AU - Seeger, Thalia S.
AU - Kayser, Sarah
AU - Pham, Kien Binh
AU - Jutzi, Jonas S.
AU - Ganzenmüller, Lucas
AU - Steinemann, Doris
AU - Schlegelberger, Brigitte
AU - Wagner, Julia M.
AU - Jung, Manfred
AU - Will, Britta
AU - Steidl, Ulrich
AU - Aumann, Konrad
AU - Werner, Martin
AU - Günther, Thomas
AU - Schüle, Roland
AU - Rambaldi, Alessandro
AU - Pahl, Heike L.
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20110540
DO - 10.1084/jem.20110540
M3 - Article
C2 - 22231305
AN - SCOPUS:84856911269
SN - 0022-1007
VL - 209
SP - 35
EP - 50
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -