title: Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency.
abstract: Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were identified in hematopoietic malignancies. To clarify the role(s) of EED in adult hematopoiesis and leukemogenesis, we generated Eed conditional knockout (Eed(Δ/Δ)) mice. Eed(Δ/Δ) mice died in a short period with rapid decrease of hematopoietic cells. Hematopoietic stem/progenitor cells (HSPCs) were markedly decreased with impaired bone marrow (BM) repopulation ability. Cell cycle analysis of HSPCs demonstrated increased S-phase fraction coupled with suppressed G0/G1 entry. Genes encoding cell adhesion molecules are significantly enriched in Eed(Δ/Δ) HSPCs, and consistently, Eed(Δ/Δ) HSPCs exhibited increased attachment to a major extracellular matrix component, fibronectin. Thus, EED deficiency increases proliferation on one side but promotes quiescence possibly by enhanced adhesion to the hematopoietic niche on the other, and these conflicting events would lead to abnormal differentiation and functional defect of Eed(Δ/Δ) HSPCs. In addition, Eed haploinsufficiency induced hematopoietic dysplasia, and Eed heterozygous mice were susceptible to malignant transformation and developed leukemia in cooperation with Evi1 overexpression. Our results demonstrated differentiation stage-specific and dose-dependent roles of EED in normal hematopoiesis and leukemogenesis.
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.|Department of Urology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Yamasaki
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nakata
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sera
authors.affiliation: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nagamachi
authors.affiliation: Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Miyama
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.affiliation: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kanai
authors.affiliation: Department of Pathology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.affiliation: Health Care Center and Graduate School of Humanities and Sciences, Institute of Environmental Science for Human Life, Ochanomizu University, 2-1-1 Otsuka Bunkyo-ku, Tokyo 112-8611, Japan.
authors.forename: Zen-Ichiro
authors.initials: Z
authors.lastname: Honda
authors.affiliation: Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ichinohe
authors.affiliation: Department of Urology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Matsubara
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore Center for Translational Medicine, 14 Medical Drive, #12-01, 117599, Singapore.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002448:Cell Adhesion; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D057895:Haploinsufficiency; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006579:Heterozygote; D006657:Histones; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; C107275:Eed protein, mouse; D005353:Fibronectins; D006657:Histones; D034741:RNA, Small Interfering; D063151:Polycomb Repressive Complex 2