A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2.
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.
Department of Experimental Anaesthesiology, Center for Clinical Research, University Hospital Freiburg, Germany.
Kai B
KB
Kaufmann
Albert
A
Gründer
Tobias
T
Hadlich
Julius
J
Wehrle
Monika
M
Gothwal
Ruzhica
R
Bogeska
Thalia S
TS
Seeger
Sarah
S
Kayser
Kien-Binh
KB
Pham
Jonas S
JS
Jutzi
Lucas
L
Ganzenmüller
Doris
D
Steinemann
Brigitte
B
Schlegelberger
Julia M
JM
Wagner
Manfred
M
Jung
Britta
B
Will
Ulrich
U
Steidl
Konrad
K
Aumann
Martin
M
Werner
Thomas
T
Günther
Roland
R
Schüle
Alessandro
A
Rambaldi
Heike L
HL
Pahl
D000818:Animals; D001772:Blood Cell Count; D001773:Blood Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D050983:NF-E2 Transcription Factor / Q000235:genetics*; D010641:Phenotype
D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D050983:NF-E2 Transcription Factor