Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation
Year: 2018
Type: article
Abstract: 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
Authors: Reina Nagase, Daichi Inoue, Alessandro Pastore, Takeshi Fujino, Hsin-An Hou, Norimasa Yamasaki, Susumu Goyama, Makoto Saika, Akinori Kanai, Yasuyuki Sera, Sayuri Horikawa, Yasunori Ota, Shuhei Asada, Yasutaka Hayashi, Kimihito Cojin Kawabata, Reina Takeda, Hwei-Fang Tien, Hiroaki Honda, Omar Abdel-Wahab, Toshio Kitamura
Institutions: Institute of Medical Science, The University of Tokyo, The University of Tokyo, Memorial Sloan Kettering Cancer Center, National Taiwan University Hospital, Hiroshima University, Research Institute for Radiation Biology and Medicine, Hiroshima University, Tokyo Women's Medical University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: Comprehensive elucidation of MDS (myelodysplastic syndromes) pathogenesis, G349768430, UNDERSTANDING THE TARGETING EPIGENETIC ALTERATIONS IN AQUIRED BONW MARROW FAILURE, G4119534169, The effects of ionizing radiation on early development stage of the fertilized egg, 造血幹細胞老化におけるヒストンＨ３Ｋ２７脱メチル化酵素ＵＴＸの機能解析, G7748957729, G8409963661, The role of SETBP1 mutation in leukemic transformation, Cancer Center Support Grant
OpenAlex ID: W2797367925