Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 215, Issue 6, Pages 1729-1747Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20171151
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Funding
- Friends of Leukemia Research Fund
- Japan Society for the Promotion of Science KAKENHI [26893051, 15H04855]
- Overseas Research Fellowships
- Leukemia and Lymphoma Society
- Tokyo Biochemical Research Foundation
- Uehara Memorial Foundation
- US Department of Defense Bone Marrow Failure Research Program [W81XWH-12-1-0041]
- Edward P. Evans Foundation
- Taub Foundation
- Starr Foundation [I8-A8-075, I9-A9-059]
- Grants-in-Aid for Scientific Research [17H05634, 26893051, 15H04855] Funding Source: KAKEN
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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.
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