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

   


Authors: Nagase, R.; Inoue, D.; Pastore, A.; Fujino, T.; Hou, H. A.; Yamasaki, N.; Goyama, S.; Saika, M.; Kanai, A.; Sera, Y.; Horikawa, S.; Ota, Y.; Asada, S.; Hayashi, Y.; Kawabata, K. C.; Takeda, R.; Tien, H. F.; Honda, H.; Abdel-Wahab, O.; Kitamura, T.
Article Title: Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation
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.
Journal Title: Journal of Experimental Medicine
Volume: 215
Issue: 6
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2018-06-01
Start Page: 1729
End Page: 1747
Language: English
DOI: 10.1084/jem.20171151
PROVIDER: scopus
PMCID: PMC5987913
PUBMED: 29643185
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85048104998&doi=10.1084%2fjem.20171151&partnerID=40&md5=082804c1a65b82e85a60cf94db6a1fa9
Notes: Article -- Export Date: 2 July 2018 -- Source: Scopus
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MSK Authors
  1. Omar Ibrahim Abdel-Wahab
    573 Abdel-Wahab
  2. Alessandro Pastore
    55 Pastore
  3. Daichi Inoue
    27 Inoue
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