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

Author

Listed:
  • 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))

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.

Suggested Citation

  • A. Herrera-Merchan & L. Arranz & J.M. Ligos & A. de Molina & O. Dominguez & S. Gonzalez, 2012. "Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1623
    DOI: 10.1038/ncomms1623
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