ウツギサワ タイジユ   UTSUGISAWA Taiju
  槍澤 大樹
   所属   医学部 医学科(東京女子医科大学病院)
   職種   講師
論文種別 原著
言語種別 英語
査読の有無 査読あり
表題 KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells.
掲載誌名 正式名:Experimental hematology
略  称:Exp Hematol
ISSNコード:18732399/0301472X
掲載区分国外
巻・号・頁 73,pp.25-37.e8
著者・共著者 Kohara Hiroshi, Utsugisawa Taiju, Sakamoto Chika, Hirose Lisa, Ogawa Yoshie, Ogura Hiromi, Sugawara Ai, Liao Jiyuan, Aoki Takako, Iwasaki Takuya, Asai Takayoshi, Doisaki Sayoko, Okuno Yusuke, Muramatsu Hideki, Abe Takaaki, Kurita Ryo, Miyamoto Shohei, Sakuma Tetsushi, Shiba Masayuki, Yamamoto Takashi, Ohga Shouichi, Yoshida Kenichi, Ogawa Seishi, Ito Etsuro, Kojima Seiji, Kanno Hitoshi, Tani Kenzaburo
担当区分 2nd著者
発行年月 2019/05
概要 Krüppel-like factor 1 (KLF1), a transcription factor controlling definitive erythropoiesis, is involved in sequential control of terminal cell division and enucleation via fine regulation of key cell cycle regulator gene expression in erythroid lineage cells. Type IV congenital dyserythropoietic anemia (CDA) is caused by a monoallelic mutation at the second zinc finger of KLF1 (c.973G>A, p.E325K). We recently diagnosed a female patient with type IV CDA with the identical missense mutation. To understand the mechanism underlying the dyserythropoiesis caused by the mutation, we generated induced pluripotent stem cells (iPSCs) from the CDA patient (CDA-iPSCs). The erythroid cells that differentiated from CDA-iPSCs (CDA-erythroid cells) displayed multinucleated morphology, absence of CD44, and dysregulation of the KLF1 target gene expression. In addition, uptake of bromodeoxyuridine by CDA-erythroid cells was significantly decreased at the CD235a+/CD71+ stage, and microarray analysis revealed that cell cycle regulator genes were dysregulated, with increased expression of negative regulators such as CDKN2C and CDKN2A. Furthermore, inducible expression of the KLF1 E325K, but not the wild-type KLF1, caused a cell cycle arrest at the G1 phase in CDA-erythroid cells. Microarray analysis of CDA-erythroid cells and real-time polymerase chain reaction analysis of the KLF1 E325K inducible expression system also revealed altered expression of several KLF1 target genes including erythrocyte membrane protein band 4.1 (EPB41), EPB42, glutathione disulfide reductase (GSR), glucose phosphate isomerase (GPI), and ATPase phospholipid transporting 8A1 (ATP8A1). Our data indicate that the E325K mutation in KLF1 is associated with disruption of transcriptional control of cell cycle regulators in association with erythroid membrane or enzyme abnormalities, leading to dyserythropoiesis.
DOI 10.1016/j.exphem.2019.03.001
PMID 30876823