title: Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation.
abstract: Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2. Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2-null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9. These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners.
authors: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors: Goro
authors: G
authors: Sashida
authors: 1] Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan [2].
authors: Hironori
authors: H
authors: Harada
authors: Division of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors: Hirotaka
authors: H
authors: Matsui
authors: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors: Motohiko
authors: M
authors: Oshima
authors: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors: Makiko
authors: M
authors: Yui
authors: 1] Division of Radiation Information Registry, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan [2].
authors: Yuka
authors: Y
authors: Harada
authors: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] Department of Hematology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Satomi
authors: S
authors: Tanaka
authors: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors: Makiko
authors: M
authors: Mochizuki-Kashio
authors: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors: Changshan
authors: C
authors: Wang
authors: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors: Atsunori
authors: A
authors: Saraya
authors: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] Department of Hematology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Tomoya
authors: T
authors: Muto
authors: 1] Division of Pathology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA [2] Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA.
authors: Yoshihiro
authors: Y
authors: Hayashi
authors: Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Kotaro
authors: K
authors: Suzuki
authors: Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Hiroshi
authors: H
authors: Nakajima
authors: Division of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors: Toshiya
authors: T
authors: Inaba
authors: 1] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan [2] Laboratory for Lymphocyte Development, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors: Haruhiko
authors: H
authors: Koseki
authors: 1] Division of Pathology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA [2] Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA.
authors: Gang
authors: G
authors: Huang
authors: Division of Cellular Therapy and Division of Stem Cell Signaling, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo 108-8639, Japan.
authors: Toshio
authors: T
authors: Kitamura
authors: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors: Atsushi
authors: A
authors: Iwama
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology; D002471:Cell Transformation, Neoplastic; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D018398:Homeodomain Proteins; C493726:Runx1 protein, mouse; C097899:homeobox protein HOXA9; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2