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Myelodysplastic syndrome

High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis

Leukemia volume 32, pages 419–428 (2018)Cite this article

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Abstract

Both proto-oncogenic and tumor-suppressive functions have been reported for enhancer of zeste homolog 2 (EZH2). To investigate the effects of its inactivation, a mutant EZH2 lacking its catalytic domain was prepared (EZH2-dSET). In a mouse bone marrow transplant model, EZH2-dSET expression in bone marrow cells induced a myelodysplastic syndrome (MDS)-like disease in transplanted mice. Analysis of these mice identified Abcg2 as a direct target of EZH2. Intriguingly, Abcg2 expression alone induced the same disease in the transplanted mice, where stemness genes were enriched. Interestingly, ABCG2 expression is specifically high in MDS patients. The present results indicate that ABCG2 de-repression induced by EZH2 mutations have crucial roles in MDS pathogenesis.

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Acknowledgements

We thank Hiroshi Kimura for antibodies for histones, and Goro Sashida and Atsushi Iwama for advice in EZH2 experiments. We also thank Yosuke Ogata for technical assistance in the analysis of clinical specimens. This study was supported by grants in aid from the Ministry of Education, Science, Technology, Sports and Culture, Japan (no. 23249051 and no. 15H04855).

Author contributions

Performed the experiments: KCK, YH, DI, HS, HM, HH and YH; analyzed the data: KCK, YH and YH; contributed reagents/materials/analysis tools: HA, HH and YH; wrote paper: KCK and TK; secured funding: YT, SG and TK; data interpretation: all other authors.

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Authors and Affiliations

  1. Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan

    K C Kawabata, Y Hayashi, D Inoue, T Fukuyama, Y Tanaka, S Asada, T Fukushima, R Nagase, R Takeda, J Kitaura, S Goyama & T Kitamura

  2. Division of Hematology/Medical Oncology, Department of Medicine, Weill-Cornell Medical College, Cornell University, New York, NY, USA

    K C Kawabata

  3. Department of Medicine, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    D Inoue

  4. Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan

    H Meguro & H Harada

  5. Division of Hematology, Department of Medicine, Juntendo University, Bunkyo, Japan

    H Sakurai, Y Harada & H Harada

  6. Division of Hemalogy, Shizuoka Hospital, Juntendo University, Izunokuni, Japan

    H Sakurai

  7. Department of Clinical Laboratory Medicine, Faculty of Health Science Technology, Bunkyo Gakuin University, Bunkyo, Japan

    Y Harada

  8. Atopy Research Center, Juntendo University. School of Medicine, Bunkyo-ku, Japan

    J Kitaura

  9. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro, Japan

    H Aburatani

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  1. K C Kawabata
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Correspondence to T Kitamura.

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Kawabata, K., Hayashi, Y., Inoue, D. et al. High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis. Leukemia 32, 419–428 (2018). https://doi.org/10.1038/leu.2017.227

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