title: Systematic Cellular Disease Models Reveal Synergistic Interaction of Trisomy 21 and GATA1 Mutations in Hematopoietic Abnormalities.
abstract: Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect of these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD) in Down syndrome, which is characteristically associated with somatic mutations in GATA1. To better understand functional interplay between trisomy 21 and GATA1 mutations in hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs) and genome-editing technologies. Comparative analysis of these engineered iPSCs demonstrated that trisomy 21 perturbed hematopoietic development through the enhanced production of early hematopoietic progenitors and the upregulation of mutated GATA1, resulting in the accelerated production of aberrantly differentiated cells. These effects were mediated by dosage alterations of RUNX1, ETS2, and ERG, which are located in a critical 4-Mb region of chromosome 21. Our study provides insight into the genetic synergy that contributes to multi-step leukemogenesis.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Banno
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo 102-0083, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Omori
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Nawa
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Nakagawa
authors.affiliation: Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8562, Japan.
authors.forename: Manami
authors.initials: M
authors.lastname: Ohtaka
authors.affiliation: Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8562, Japan.
authors.forename: Mahito
authors.initials: M
authors.lastname: Nakanishi
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sakuma
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.affiliation: Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.affiliation: Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Kokubu
authors.affiliation: Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Takeda
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Arahori
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. Electronic address: ykitaba@ped.med.osaka-u.ac.jp.
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Kitabatake
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
mesh_terms: D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics*; D004843:Epistasis, Genetic; D004920:Erythropoiesis / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000235:genetics*; D055786:Gene Knockout Techniques; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008533:Megakaryocytes / Q000473:pathology; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D017393:RNA Editing / Q000235:genetics; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D050982:GATA1 Transcription Factor; D014157:Transcription Factors