Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease

A. Herrera-Merchan, L. Arranz, J.M. Ligos, A. de Molina, O. Dominguez and S. Gonzalez ()
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A. Herrera-Merchan: Stem Cell Aging Group, Spanish National Cardiovascular Research Center (CNIC)
L. Arranz: Stem Cell Aging Group, Spanish National Cardiovascular Research Center (CNIC)
J.M. Ligos: Cellomic Unit, Spanish National Cardiovascular Research Center (CNIC)
A. de Molina: Animal Unit, Spanish National Cardiovascular Research Center (CNIC)
O. Dominguez: Genomics Unit, Spanish National Cancer Research Center (CNIO)
S. Gonzalez: Stem Cell Aging Group, Spanish National Cardiovascular Research Center (CNIC)

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract Recent evidence shows increased and decreased expression of Ezh2 in cancer, suggesting a dual role as an oncogene or tumour suppressor. To investigate the mechanism by which Ezh2-mediated H3K27 methylation leads to cancer, we generated conditional Ezh2 knock-in (Ezh2-KI) mice. Here we show that induced Ezh2 haematopoietic expression increases the number and proliferation of repopulating haematopoietic stem cells. Ezh2-KI mice develop myeloproliferative disorder, featuring excessive myeloid expansion in bone marrow and spleen, leukocytosis and splenomegaly. Competitive and serial transplantations demonstrate progressive myeloid commitment of Ezh2-KI haematopoietic stem cells. Transplanted self-renewing haematopoietic stem cells from Ezh2-KI mice induce myeloproliferative disorder, suggesting that the Ezh2 gain-of-function arises in the haematopoietic stem cell pool, and not at later stages of myelopoiesis. At the molecular level, Ezh2 regulates haematopoietic stem cell-specific genes such as Evi-1 and Ntrk3, aberrantly found in haematologic malignancies. These results demonstrate a stem cell-specific Ezh2 oncogenic role in myeloid disorders, and suggest possible therapeutic applications in Ezh2-related haematological malignancies.

Date: 2012
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DOI: 10.1038/ncomms1623

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