title: Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease.
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.
authors.affiliation: Stem Cell Aging Group, Spanish National Cardiovascular Research Center (CNIC), E-28029 Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Herrera-Merchan
authors.forename: L
authors.initials: L
authors.lastname: Arranz
authors.forename: J M
authors.initials: JM
authors.lastname: Ligos
authors.forename: A
authors.initials: A
authors.lastname: de Molina
authors.forename: O
authors.initials: O
authors.lastname: Dominguez
authors.forename: S
authors.initials: S
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002469:Cell Separation; D017690:Cell Transplantation; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006657:Histones / Q000235:genetics; D007107:Immune System; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009196:Myeloproliferative Disorders / Q000235:genetics; D063151:Polycomb Repressive Complex 2; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D019076:Transgenes
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2