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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Myelodysplastic syndromes are induced by histone methylation–altering ASXL1 mutations

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 6

ASXL1 mutations collaborated with the N-Ras activating mutation in inducing myeloid leukemia.

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ASXL1 mutations collaborated with the N-Ras activating mutation in indu...
(A) Kaplan-Meier analysis for the survival of mice that received transplants of BM cells transduced with pMYs-N-Ras-G12V-IG and pMYs-INGFR (N-Ras-G12V + mock, n = 4, blue line) and pMYs-N-Ras-G12V-IG and pMYs-ASXL1-MT2-INGFR (N-Ras-G12V + ASXL1-MT, n = 6, red line). P values were calculated using a log-rank test. (B) Cytospin preparations of BM cells derived from mice transplanted with N-Ras-G12V + mock and N-Ras-G12V + ASXL1-MT were stained with Giemsa. Representative photographs are shown. Original magnification, ×400; scale bars: 20 μm. (C and D) Mice transplanted with N-Ras-G12V/ASXL1-MT displayed increased numbers of leukemic blasts in BM (C) and hepatomegaly and splenomegaly (D), although the differences in spleen weight were not statistically significant. P values were calculated using the Student’s t test (C) or Cochran-Cox test (D). (E) Macroscopic findings of sacrificed mice transplanted with BM cells transduced with the indicated construct. Representative photographs are shown. (F) Mice transplanted with N-Ras-G12V/mock and N-Ras-G12V/ASXL1-MT displayed severe anemia and leukopenia to a similar extent. (G) qRT-PCR revealed an increased expression of Hoxa9 and decreased expression of Clec5a in the BM of mice transplanted with N-Ras-G12V/ASXL1-MT. P values were calculated using the Cochran-Cox test. (H) Flow cytometric analysis of BM cells derived from sacrificed mice transduced with indicated constructs.