演題詳細

一般口演 / Oral Session

【E】一般口演 33 (Oral Session 33) :MDS/MPN:Basic Research 1

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日程
2013年10月11日(金)
時間
14:25 - 15:25
会場
第14会場 / Room No.14 (札幌市教育文化会館 3F 研修室305)
座長・司会
桐戸 敬太 (Keita Kirito):1
1:Department of Hematology, University of Yamanashi, Japan
 
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Concurrent depletion of Ezh2 and Tet2 accelerates development of myelodysplastic disorders in mice

演題番号 : OS-1-168

武藤 朋也 (Tomoya Muto):1,2,3、指田 吾郎 (Goro Sashida):1,4、大島 基彦 (Motohiko Oshima):1,4、Wendt George:1,10、望月(樫尾) 牧子 (Makiko Mochizuki-Kashio):1,4、永田 安伸 (Yasunobu Nagata):5、真田 昌 (Masashi Sanada):5、宮城 聡 (Satoru Miyagi):1,4、更屋 敦則 (Atsunori Saraya):1,4、神尾 明日香 (Asuka Kamio):6、永江 玄太 (Genta Nagae):6、中世古 知昭 (Chiaki Nakaseko):2,3、横手 幸太郎 (Koutaro Yokote):2、下田 和哉 (Kazuya Shimoda):7、古関 明彦 (Haruhiko Koseki):4,8、鈴木 穣 (Yutaka Suzuki):9、菅野 純夫 (Sumio Sugano):9、油谷 浩幸 (Hiroyuki Aburatani):6、小川 誠司 (Seishi Ogawa):5、岩間 厚志 (Atsushi Iwama):1,4

1:Department of Cellular and Molecular Medicine, Chiba University, Japan、2:Department of Clinical Cell Biology and Medicine, Chiba University, Japan、3:Department of Hematology, Chiba University Hospital, Japan、4:Japan Science and Technology Agency, CREST, Japan、5:Cancer Genomics Project, Tokyo Univ, Japan、6:Genome Science Division, Tokyo Univ, Japan、7:Department of Gastroenterology and Hematology, Miyazaki University, Japan、8:Research Center for Allergy and Immunology, RIKEN, Japan、9:Laboratory of Functional Genomics, Tokyo Univ, Japan、10:ITO Foundation for International Education Exchange, Japan

 

Background: Inactivating somatic mutations in polycomb-group (PcG) genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN) and MDS/MPN overlap disorders. While these mutations suggest a tumor suppressor function of PRC2-related genes in these diseases, both the impact of each PcG mutation and its interplay with coinciding mutations remains largely unknown.
Methods: Genomic DNAs from 199 patients with MDS and related neoplasms were analyzed for mutations of EZH2, ASXL1 and TET2 genes by high-throughput sequencing. Furthermore, we examined the Ezh2-deficient mice and also tested the impact of concurrent depletion of Ezh2 and Tet2 on hematopoiesis.
Results: In our patient cohort, PcG mutations were also found and often coincided with TET2 mutations. In line with these findings, deletion of Ezh2 alone was enough to induce MDS/MPN-like diseases in mice. Of note, concurrent depletion of Ezh2 and Tet2 markedly accelerated the development of not only MDS/MPN but also MDS and all the compound mice died of infection by 10 months. Comprehensive analyses of the epigenome in hematopoietic progenitor cells revealed that upon deletion of Ezh2, key developmental regulator genes were kept transcriptionally repressed via the compensatory action of Ezh1 while several oncogenic direct and indirect PcG targets became derepressed.
Conclusion: Our findings provide the first evidence of the tumor repressor function of EZH2 and demonstrate the cooperative effect of concurrent gene mutations in the pathogenesis of myelodysplasia.

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