ホンダ ヒロアキ
  本田 浩章
   所属   研究施設 研究施設
   職種   教授
論文種別 原著
言語種別 英語
査読の有無 査読あり
表題 Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation.
掲載誌名 正式名:The Journal of experimental medicine
略  称:J Exp Med
ISSNコード:15409538/00221007
掲載区分国外
巻・号・頁 215(6),1729-1747頁
著者・共著者 Nagase Reina, Inoue Daichi, Pastore Alessandro, Fujino Takeshi, Hou Hsin-An, Yamasaki Norimasa, Goyama Susumu, Saika Makoto, Kanai Akinori, Sera Yasuyuki, Horikawa Sayuri, Ota Yasunori, Asada Shuhei, Hayashi Yasutaka, Kawabata Kimihito Cojin, Takeda Reina, Tien Hwei-Fang, Honda Hiroaki, Abdel-Wahab Omar, Kitamura Toshio
発行年月 2018/06
概要 Additional sex combs like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. Chromatin immunoprecipitation followed by next-generation sequencing analysis demonstrated opposing effects of wild-type and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.
DOI 10.1084/jem.20171151
PMID 29643185