A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2
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A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2. / 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.
in: J EXP MED, Jahrgang 209, Nr. 1, 16.01.2012, S. 35-50.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 - 2012/1/16
Y1 - 2012/1/16
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.
KW - Animals
KW - Blood Cell Count
KW - Blood Cells
KW - Cell Differentiation
KW - Chromatin
KW - Disease Models, Animal
KW - Disease Progression
KW - Gene Expression
KW - Gene Expression Regulation
KW - Hematopoietic Stem Cells
KW - Histone Deacetylase Inhibitors
KW - Humans
KW - Leukemia
KW - Mice
KW - Mice, Transgenic
KW - Myeloproliferative Disorders
KW - NF-E2 Transcription Factor
KW - Phenotype
U2 - 10.1084/jem.20110540
DO - 10.1084/jem.20110540
M3 - SCORING: Journal article
C2 - 22231305
VL - 209
SP - 35
EP - 50
JO - J EXP MED
JF - J EXP MED
SN - 0022-1007
IS - 1
ER -