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Myelodysplastic syndromes are induced by histone methylation–altering ASXL1 mutations

J Clin Invest. doi:10.1172/JCI70739
Daichi Inoue1, Jiro Kitaura1, Katsuhiro Togami1, Koutarou Nishimura1, Yutaka Enomoto1, Tomoyuki Uchida1, Yuki Kagiyama1, Kimihito Cojin Kawabata1, Fumio Nakahara1, Kumi Izawa1, Toshihiko Oki1,2, Akie Maehara1, Masamichi Isobe1, Akiho Tsuchiya1, Yuka Harada3, Hironori Harada4, Takahiro Ochiya5, Hiroyuki Aburatani6, Hiroshi Kimura7, Felicitas Thol8, Michael Heuser8, Ross L. Levine9, Omar Abdel-Wahab9 and Toshio Kitamura1,2
1Division of Cellular Therapy, Advanced Clinical Research Center, and 2Division of Stem Cell Signaling, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 3Division of Radiation Information Registry and 4Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. 5Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan. 6Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan. 7Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan. 8Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. 9Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

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.