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J Exp Med. 2018 Jun 4;215(6):1729-1747. doi: 10.1084/jem.20171151. Epub 2018 Apr 11.

Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation.

Author information

1
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
2
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan inoued@mskcc.org.
3
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY.
4
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
5
Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
6
Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
7
Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
8
Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Tokyo Women's Medical University, Tokyo, Japan.
9
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan kitamura@ims.u-tokyo.ac.jp.

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.

PMID:
29643185
PMCID:
PMC5987913
[Available on 2018-12-04]
DOI:
10.1084/jem.20171151

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