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Myelodysplastic syndromes are induced by histone methylation–altering ASXL1 mutations
Daichi Inoue, … , Omar Abdel-Wahab, Toshio Kitamura
Daichi Inoue, … , Omar Abdel-Wahab, Toshio Kitamura
Published October 8, 2013
Citation Information: J Clin Invest. 2013;123(11):4627-4640. https://doi.org/10.1172/JCI70739.
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Research Article Hematology Article has an altmetric score of 11

Myelodysplastic syndromes are induced by histone methylation–altering ASXL1 mutations

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Abstract

Recurrent mutations in the gene encoding additional sex combs-like 1 (ASXL1) are found in various hematologic malignancies and associated with poor prognosis. In particular, ASXL1 mutations are common in patients with hematologic malignancies associated with myelodysplasia, including myelodysplastic syndromes (MDSs), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal–truncating Asxl1 mutations (ASXL1-MTs) inhibited myeloid differentiation and induced MDS-like disease in mice. ASXL1-MT mice displayed features of human-associated MDS, including multi-lineage myelodysplasia, pancytopenia, and occasional progression to overt leukemia. ASXL1-MT resulted in derepression of homeobox A9 (Hoxa9) and microRNA-125a (miR-125a) expression through inhibition of polycomb repressive complex 2–mediated (PRC2-mediated) methylation of histone H3K27. miR-125a reduced expression of C-type lectin domain family 5, member a (Clec5a), which is involved in myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1-MT, while CLEC5A expression was generally low. Thus, ASXL1-MT–induced MDS-like disease in mice is associated with derepression of Hoxa9 and miR-125a and with Clec5a dysregulation. Our data provide evidence for an axis of MDS pathogenesis that implicates both ASXL1 mutations and miR-125a as therapeutic targets in MDS.

Authors

Daichi Inoue, Jiro Kitaura, Katsuhiro Togami, Koutarou Nishimura, Yutaka Enomoto, Tomoyuki Uchida, Yuki Kagiyama, Kimihito Cojin Kawabata, Fumio Nakahara, Kumi Izawa, Toshihiko Oki, Akie Maehara, Masamichi Isobe, Akiho Tsuchiya, Yuka Harada, Hironori Harada, Takahiro Ochiya, Hiroyuki Aburatani, Hiroshi Kimura, Felicitas Thol, Michael Heuser, Ross L. Levine, Omar Abdel-Wahab, Toshio Kitamura

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Figure 4

ASXL1 mutations induce MDS-like symptoms in a mouse BMT model.

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ASXL1 mutations induce MDS-like symptoms in a mouse BMT model.
 
(A) Pe...
(A) Percentage of chimerism of donor cells in peripheral blood (PB). The chimerism of Ly5.1 donor–derived GFP-positive cells in PB (mean ± SEM) was examined after transplantation: mock, n = 6; ASXL1-MT, n = 12; ASXL1-WT, n = 6. (B) Percentages of CD11b-positive or B220-positive cells related to GFP positivity in the BM of the transplanted mice determined by flow cytometric analyses. Samples were obtained from mice with pMYs-FLAG-ASXL1-MT2-IG, sacrificed 6 months after transplantation (n = 5). (C) Dysplasias of hematopoietic cells in mice receiving transplants of ASXL1 mutants were observed. Scale bars: 10 μm. (D) Kaplan-Meier analysis for the survival of mice that received transplants of BM cells transduced with pMYs-IG (mock, n = 13, blue line) and pMYs-FLAG-ASXL1-MT2-IG (ASXL1-MT, n = 25, red line). P values were calculated using a log-rank test. (E) Flow cytometric analyses of BM cells derived from mice with ASXL1-MT. (F) Mice transplanted with ASXL1-MT2 (ASXL1-MT, n = 11) displayed progressive pancytopenia, macrocytosis, and hyperplastic BM and increased splenomegaly compared with mice transplanted with empty vector (mock, n = 5). BM cells were isolated from the femurs and tibias of the sacrificed mice. (G) Blood count data, including white blood cells (WBC), hemoglobin (Hb), and platelets (PLT), at 3, 6, or 12 months after transplantation are indicated (mean ± SEM). Mock, n = 6; ASXL1-MT, n = 12. *P < 0.05.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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