title: Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies.
abstract: Infants with Down syndrome (DS) are at a high risk of developing transient abnormal myelopoiesis (TAM). A GATA1 mutation leading to the production of N-terminally truncated GATA1 (GATA1s) in early megakaryocyte/erythroid progenitors is linked to the onset of TAM and cooperated with the effect of trisomy 21 (Ts21). To gain insights into the underlying mechanisms of the progression to TAM in DS patients, we generated human pluripotent stem cells harbouring Ts21 and/or GATA1s by combining microcell-mediated chromosome transfer and genome editing technologies. In vitro haematopoietic differentiation assays showed that the GATA1s mutation blocked erythropoiesis irrespective of an extra chromosome 21, while Ts21 and the GATA1s mutation independently perturbed megakaryopoiesis and the combination of Ts21 and the GATA1s mutation synergistically contributed to an aberrant accumulation of skewed megakaryocytes. Thus, the DS model cells generated by these two technologies are useful in assessing how GATA1s mutation is involved in the onset of TAM in patients with DS.
authors.affiliation: 1] Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan; Tel: +81-859-38-6219 [2] Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Yuwna
authors.initials: Y
authors.lastname: Yakura
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan; Tel: +81-859-38-6219.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Abe
authors.affiliation: 1] Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan [2] Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Osaki
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Naoyo
authors.initials: N
authors.lastname: Kajitani
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Kazuki
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Takehara
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan; Tel: +81-859-38-6219.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Honma
authors.affiliation: Department of Embryonic Stem Cell Research, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Suemori
authors.affiliation: Division of Stem Cell Therapy, Center for Stem Cell Biology and Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sakuma
authors.affiliation: Department of Pediatrics, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.affiliation: Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Shimizu
authors.affiliation: Division of Stem Cell Therapy, Center for Stem Cell Biology and Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: 1] Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan; Tel: +81-859-38-6219 [2] Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics / Q000503:physiopathology*; D050982:GATA1 Transcription Factor / Q000235:genetics; D005818:Genetic Engineering; D015894:Genome, Human; D006410:Hematopoiesis; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D007955:Leukemoid Reaction / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D014162:Transfection
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human