Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation
Journal
Journal of Experimental Medicine
Journal Volume
215
Journal Issue
6
Pages
1729-1747
Date Issued
2018
Author(s)
Nagase R.
Inoue D.
Pastore A.
Fujino T.
Yamasaki N.
Goyama S.
Saika M.
Kanai A.
Sera Y.
Horikawa S.
Ota Y.
Asada S.
Hayashi Y.
Kawabata K.C.
Takeda R.
Honda H.
Abdel-Wahab O.
Kitamura T.
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. ? 2018 Nagase et al.
SDGs
Other Subjects
transcription factor RUNX1; ASXL1 protein, human; Asxl1 protein, mouse; histone; protein binding; repressor protein; additional sex combs like 1 gene; adult; anemia; animal experiment; animal model; Article; cancer susceptibility; chromatin immunoprecipitation; epigenetics; gene; gene expression; genetic susceptibility; genome-wide association study; hematopoiesis; hematopoietic stem cell; histone modification; human; in vivo study; leukemia; major clinical study; mouse; mutagenesis; next generation sequencing; nonhuman; priority journal; survival; thrombocytosis; acute myeloid leukemia; animal; cell transformation; gene expression regulation; gene knock-in; genetic epigenesis; genetic transcription; genetics; hematopoietic stem cell transplantation; human genome; leukemia; metabolism; mutation; myelodysplastic syndrome; nucleotide sequence; pathology; phenotype; Adult; Animals; Base Sequence; Cell Transformation, Neoplastic; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Gene Knock-In Techniques; Genome, Human; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Histones; Humans; Leukemia; Leukemia, Myeloid, Acute; Mice; Mutagenesis; Mutation; Myelodysplastic Syndromes; Phenotype; Protein Binding; Repressor Proteins; Transcription, Genetic
Publisher
Rockefeller University Press
Type
journal article