Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease.
Nat Commun, 2012/1/10;3:623.
Herrera-Merchan A[1], Arranz L, Ligos JM, de Molina A, Dominguez O, Gonzalez S
Affiliations
PMID: 22233633DOI: 10.1038/ncomms1623
Impact factor: 17.694
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.
MeSH terms
Animals; Cell Proliferation; Cell Separation; Cell Transplantation; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Histones; Immune System; Mice; Mice, Transgenic; Models, Biological; Models, Genetic; Myeloproliferative Disorders; Polycomb Repressive Complex 2; Time Factors; Transcription Factors; Transgenes
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