title: Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner.
abstract: Recent genome sequencing revealed inactivating mutations in EZH2, which encodes an enzymatic component of polycomb-repressive complex 2 (PRC2), in patients with myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and MDS/MPN overlap disorders. We herein demonstrated that the hematopoietic-specific deletion of Ezh2 in mice induced heterogeneous hematopoietic malignancies. Myelodysplasia was detected in mice following the deletion of Ezh2, and resulted in the development of MDS and MDS/MPN. Thrombocytosis was induced by Ezh2 loss and sustained in some mice with myelodysplasia. Although less frequent, Ezh2 loss also induced T-cell acute lymphoblastic leukemia and the clonal expansion of B-1a B cells. Gene expression profiling showed that PRC2 target genes were derepressed upon the deletion of Ezh2 in hematopoietic stem and progenitor cells, but were largely repressed during the development of MDS and MDS/MPN. Chromatin immunoprecipitation-sequence analysis of trimethylation of histone H3 at lysine 27 (H3K27me3) revealed a compensatory function of Ezh1, another enzymatic component of PRC2, in this process. The deletion of Ezh1 alone did not cause dysplasia or any hematologic malignancies in mice, but abolished the repopulating capacity of hematopoietic stem cells when combined with Ezh2 loss. These results clearly demonstrated an essential role of Ezh1 in the pathogenesis of hematopoietic malignancies induced by Ezh2 insufficiency, and highlighted the differential functions of Ezh1 and Ezh2 in hematopoiesis.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
authors.forename: Makiko
authors.initials: M
authors.lastname: Mochizuki-Kashio
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Aoyama
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan;
authors.forename: Goro
authors.initials: G
authors.lastname: Sashida
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
authors.forename: Motohiko
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan; and.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Tomioka
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
authors.forename: Tomoya
authors.initials: T
authors.lastname: Muto
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; College of Life Sciences, Inner Mongolia University, Hohhot, China.
authors.forename: Changshan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D000071221:Enhancer of Zeste Homolog 2 Protein; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; C498408:Ezh1 protein, mouse; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2