Analysis of cartilage-specific IDH mutant mice for explication of underlying mechanism in chondrosarcoma development

• Project/Area Number: 15K18398
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: Hirata Makoto 東京大学, 医科学研究所, 特任助教 (50401071)
• Research Collaborator: Alman Benjamin A.
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 軟骨腫瘍 / イソクエン酸デヒドロゲナーゼ / 腫瘍 / 軟骨 / 代謝

Outline of Final Research Achievements

Central chondrosarcomas are known to harbor frequent mutation in IDH1 or IDH2 genes. The objective of the current study is to generate genetically-engineered mice expressing mutant IDH1 or IDH2 specifically in cartilage and to elucidate the underlying mechanism of chondrosarcoma occurrence and development. The mutant IDH1 or IDH2 mice exhibited dwarfism as compared to their wild-type littermate, with morphologically abnormal growth plate cartilage. Of note, the IDH2 mutant mice harbored severer phenotype in cartilage than the IDH1 mutant mice. The mutant IDH1 or IDH2 mice with p53 deficiency were generated by crossing with p53-flox mice. No clear evidence of bone tumor development has been observed until the age of three months old.

Research Products

• [Int'l Joint Research] University of Toronto/Hospital for Sick Children/Mt. Sinai Hospital(カナダ)
• [Journal Article] Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes. (2016)
  • Author(s): Kobayashi H, Chang S, Mori D, Itoh S, Hirata M, Hosaka Y, Taniguchi Y, Okada K, Mori Y, Yano F, Chung U, Akiyama H, Kawaguchi H, Tanaka S, Saito T.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 13336-13336
  • DOI: 10.1038/ncomms13336
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype. (2016)
  • Author(s): Sato S, Tang YJ, Wei Q, Hirata M, Weng A, Han I, Okawa A, Takeda S, Whetstone H, Nadesan P, Kirsch DG, Wunder JS, Alman BA.
  • Journal Title: Cell Rep. Volume: 16 Issue: 4 Pages: 917-27
  • DOI: 10.1016/j.celrep.2016.06.058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 骨軟部腫瘍のゲノム解析 (2016)
  • Author(s): 平田 真、松田 浩一
  • Journal Title: 整形・災害外科 Volume: 59 Pages: 1345-1352
• [Journal Article] Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma. (2015)
  • Author(s): Wei Q, Tang YJ, Voisin V, Sato S, Hirata M, Whetstone H, Han I, Ailles L, Bader GD, Wunder J, Alman BA.
  • Journal Title: Oncotarget Volume: 6 Issue: 37 Pages: 40283-94
  • DOI: 10.18632/oncotarget.5375
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] D-2HG levels and IDH mutation type correlate with disease free survival in chondrosarcoma. (2016)
  • Author(s): Makoto Hirata, Nalan Gokgoz, Qingxia Wei, Shingo Sato, Yuning J. Tang, Irene L. Andrulis, Benjamin Alman, Jay Wunder
  • Organizer: CTOS2016 Annual Meeting
  • Place of Presentation: Lisbon, Portugal
  • Year and Date: 2016-11-09
  • Int'l Joint Research
• [Presentation] Mesenchymal tumors can derive from Ng2-expressing pericytes with β-catenin modulating the neoplastic phenotype. (2016)
  • Author(s): Shingo Sato, Yuning J. Tang, Qingxia Wei, Makoto Hirata, Ilkyu Han, Shu Takeda, David Kirsch, Jay Wunder, Benjamin Alman
  • Organizer: CTOS2016 Annual Meeting
  • Place of Presentation: Lisbon, Portugal
  • Year and Date: 2016-11-09
  • Int'l Joint Research
• [Presentation] Establishment of Japanese Sarcoma Genome Consortium (JSGS) for genomic analysis. (2016)
  • Author(s): Makoto Hirata, Koichi Matsuda
  • Organizer: CTOS2016 Annual Meeting
  • Place of Presentation: Lisbon, Portugal
  • Year and Date: 2016-11-09
  • Int'l Joint Research
• [Presentation] 軟骨肉腫におけるIDH1/2変異による層別化臨床情報解析 (2016)
  • Author(s): 平田 真, 松田 浩一, Benjamin Alman, Jay Wunder
  • Organizer: 第14回関東骨軟部腫瘍の基礎を語る会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-29
• [Presentation] 骨軟部腫瘍のゲノム解析 ～脱分化型脂肪肉腫の全エクソンシークエンス解析～ (2016)
  • Author(s): 平田 真、浅野 尚文、片山 琴絵、津田 祐輔、元井 亨、五嶋 孝博、岩本 幸英、小田 義直、岩田 慎太郎、西田 佳弘 、平賀 博明、比留間 徹、小林 寛、荒木 信人、河野 博隆、中川 英刀、井元 清哉、宮野 悟、山口 類、市川 仁、松田 浩一、Japan Sarcoma Genome Consortium
  • Organizer: 第13回関東骨軟部腫瘍の基礎を語る会 春のセミナー
  • Place of Presentation: 伊豆の国, 静岡
  • Year and Date: 2016-04-09