Tobias Hadlich

University Medical Center Hamburg-Eppendorf

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Peter Vandenberghe

KU Leuven

Jennifer Cassells

University of Glasgow

Sonja Loges

University Hospital Heidelberg

Leena Mukherjee

Beatson West of Scotland Cancer Centre

Carsten Bokemeyer

University Medical Center Hamburg-Eppendorf

Klaus Pantel

Universität Hamburg

Thomas Günther

Leibniz Institute of Virology (LIV)

Roland Schüle

University Medical Center Freiburg

Robert Erdmann

University Medical Center Hamburg-Eppendorf

Gunhild von Amsberg

Universität Hamburg

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Universität Hamburg

University Medical Center Hamburg-Eppendorf

University Medical Center Freiburg

University of Freiburg

Heidelberg University

University Cancer Center Hamburg

German Cancer Research Center

Center for Clinical Research (United States)

University Hospital Heidelberg

University of Glasgow

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

The Journal of Experimental Medicine (2012)

Kai Kaufmann Albert Gründer Tobias Hadlich Julius Wehrle Monika Gothwal

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.

Vorinostat

Histone deacetylase inhibitor

Myelopoiesis

10.1084/jem.20110540

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Citations (71)

Overexpression of NF-E2 In Vivo Causes Thrombocytosis and Acute Leukemia: A Murine Model of Myeloproliferative Neoplasms.

Blood (2009)

Albert Gruender Kai Kaufmann Tobias Hadlich Thomas Günther Roland Schüle

Thrombocytosis

RUNX1

10.1182/blood.v114.22.961.961