Investigation of functional roles of mutant IDH as specific mutations in cartilage-forming tumors and its application for the development of treatment

• Project/Area Number: 15H04956
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kyoto University
• Principal Investigator: Toguchida Junya 京都大学, ウイルス・再生医科学研究所, 教授 (40273502)
• Co-Investigator(Kenkyū-buntansha): 金 永輝 京都大学, 医学研究科, 特定助教 (90620344) ; 岡本 健 京都大学, 医学研究科, 准教授 (30414113) ; 池谷 真 京都大学, iPS細胞研究所, 准教授 (20442923)
• Co-Investigator(Renkei-kenkyūsha): Watanabe Akira 京都大学, iPS細胞研究所, 特定拠点助教 (60506765)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: chondrosarcoma / IDH / iPSC / p16 / IDH遺伝子 / 軟骨形成性腫瘍 / iPS細胞 / 軟骨腫瘍 / 間葉系幹細胞 / 神経幹細胞 / ヒストンメチル化 / 軟骨形成腫瘍

Outline of Final Research Achievements

Mutations of IDH gene are driver mutations in cartilage-forming tumors. To understand the mechanism of tumor specificity and functional role of IDH mutations in tumorigenesis of cartilage-forming tumors, we have performed experiments using human iPS cells. We established iPS cells with a drug-inducible mutant IDH gene in the AAVS1 locus and induced the expression of mutant IDH after the differentiation into mesenchymal stem cells (MSC). As a result, we have observed that mutant IDH has an inhibitor effect for the growth of MSC and as for the effects on differentiation, it inhibited osteogenesis and promoted the expression of cartel-related genes. To recapitulate the tumorigenesis in vitro, we further introduced the knock-out type mutations of p16 gene as a passenger mutation into IDH-AAVS-iPSCs and investigated the tumor forming capacity of iMSCs with mutant IDH and without p16 gene.

Research Products

• [Journal Article] Chondroblastoma of extra-craniofacial bones: Clinicopathological analyses of 103 cases. (2017)
  • Author(s): Konishi E, Nakashima Y, Mano M, Tomita Y, Kubo T, Araki N, Morii E, Yoshikawa H, Haga H, Toguchida J, Ueda T, Osawa M, Hoshi M, Inoue T, Aono M, Yanagisawa A.
  • Journal Title: Pathol Int Volume: 67 Issue: 10 Pages: 495-502
  • DOI: 10.1111/pin.12586
  • Peer Reviewed
• [Journal Article] BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence (2016)
  • Author(s): Hayashi, Y., Hsiao, EC., Sami, S., Lancero, M., Schlieve, CR., Nguyen, T., Yano, K., Nagahashi, A., Ikeya, M., Matsumoto, Y., Nishimura, K., Fukuda, A., Hisatake, K., Tomoda, K., Asaka, I., Toguchida, J., Conklin, BR., and Yamanaka, S
  • Journal Title: Proc. Natl. Acad. Sci. U S A Volume: 113 Pages: 13057-13062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Feasibility and efficacy of gemcitabine and docetaxel combination chemotherapy for bone and soft tissue sarcomas: multi-institutional retrospective analysis of 134 patients. (2016)
  • Author(s): Tanaka, K., Joyama, S., Chuman, H., Hiraga, H., Morioka, H., Yoshikawa, H., Hosaka, M., Takahashi, M., Kubo, T., Hatano, H., Kaya, M., Toguchida, J., Nishida, Y., Nagano, A., Tsumura, H., and Iwamoto, Y.
  • Journal Title: World J. Surg. Oncol Volume: 14 Pages: 306-306
  • Peer Reviewed
• [Journal Article] SS18-SSX, the Oncogenic Fusion Protein in Synovial Sarcoma, Is a Cellular Context-Dependent Epigenetic Modifier. (2015)
  • Author(s): Tamaki S, Fukuta M, Sekiguchi K, Jin Y, Nagata S, Hayakawa K, Hineno S, Okamoto T, Watanabe M, Woltjen K, Ikeya M, Kato T Jr, Toguchida J.
  • Journal Title: PLoS One Volume: 10 Issue: 11 Pages: e0142991-e0142991
  • DOI: 10.1371/journal.pone.0142991
  • NAID: 120005749920
  • Peer Reviewed / Open Access
• [Journal Article] Mutant IDH1 Dysregulates the Differentiation of Mesenchymal Stem Cells in Association with Gene-Specific Histone Modifications to Cartilage- and Bone-Related Genes. (2015)
  • Author(s): Jin Y, Elalaf H, Watanabe M, Tamaki S, Hineno S, Matsunaga K, Woltjen K, Kobayashi Y, Nagata S, Ikeya M, Kato T Jr, Okamoto T, Matsuda S, Toguchida J.
  • Journal Title: PLoS One Volume: 10 Issue: 7 Pages: e0131998-e0131998
  • DOI: 10.1371/journal.pone.0131998
  • NAID: 120005756272
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Primary central chondrosarcoma of long bone, limb girdle and trunk: Analysis of 174 cases by numerical scoring on histology (2015)
  • Author(s): Konishi E, Nakashima Y, Mano M, Tomita Y, Nagasaki I, Kubo T, Araki N, Haga H, Toguchida J, Ueda T, Sakuma T, Imahori M, Morii E, Yoshikawa H, Tsukamoto Y, Futani H, Wakasa K, Hoshi M, Hamada S, Takeshita H, Inoue T, Aono M, Kawabata K, Murata H, Katsura K, Urata Y, Ueda H, Yanagisawa A.
  • Journal Title: Pathology International Volume: 65 Issue: 9 Pages: 468-75
  • DOI: 10.1111/pin.12324
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Screening of BCOR-CCNB3 sarcoma using immunohistochemistry for CCNB3: A clinicopathological report of three pediatric cases. (2015)
  • Author(s): Shibayama T, Okamoto T, Nakashima Y, Kato T, Sakurai T, Minamiguchi S, Kataoka TR, Shibuya S, Yoshizawa A, Toguchida J, Haga H.
  • Journal Title: Pathol Int Volume: 65 Issue: 8 Pages: 410-414
  • DOI: 10.1111/pin.12319
  • Peer Reviewed
• [Presentation] 多能性幹細胞の肉腫研究への応用 (2017)
  • Author(s): 戸口田淳也、玉置さくら、金永輝、鎌倉武史、吉富啓之
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] 葉系幹細胞の分化及び形質転換に対するD-2-HG産生型変異IDH1の作用 (2016)
  • Author(s): 鎌倉武史、金永輝、渡辺真、松永一仁、玉置さくら、岡本健史、吉富啓之、戸口田淳也
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] EXPLORATION OF CANDIDATE GENES TO INDUCE CARTILAGE TUMORS WITH MUTANT IDH1 GENE USING IPSC (2016)
  • Author(s): Kamakura, T., Jin, Y., Matsunaga, K., Watanabe, M., Tamaki, S., Okamoto, T., Yoshitomi, H., Toguchida, J
  • Organizer: CTOS 2016 Annual Meeting
  • Place of Presentation: Lisbon（Portugal）
  • Year and Date: 2016-11-09
  • Int'l Joint Research
• [Presentation] Mutant IDH1 dysregulates the differentiation of mesenchymal stem cells in association with gene-specific histone modifications to cartilage- and bone-related genes. (2016)
  • Author(s): Jin, Y., Watanabe, M., Tamaki, S., Okamoto, T., and Toguchida, J. Mutant IDH1
  • Organizer: CTOS 21th Annual Meeting
  • Place of Presentation: Lisbon（Portugal）
  • Year and Date: 2016-11-09
  • Int'l Joint Research
• [Presentation] 変異型IDH1は遺伝子特異的なヒストン修飾を介して、間葉系幹細胞から軟骨及び骨への分化を脱制御する (2016)
  • Author(s): 金永輝、Hassan Elalaf、渡辺真、玉置さくら、日根野翔、松永一仁、Knut Woltjen, 岡本健、松田秀一、戸口田淳也
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] D-2-HG産生を伴うIDH1/2変異が及ぼす骨・軟骨分化への影響 (2016)
  • Author(s): 鎌倉武史、金永輝、渡辺真、岡本健史、吉富啓之、戸口田淳也
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] 多能性幹細胞の肉腫研究への応用 (2016)
  • Author(s): 戸口田淳也、玉置さくら、関口和也、金永輝、岡本健、松田秀一
  • Organizer: 第89回日本整形外科学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-05-12
  • Invited
• [Presentation] Mutant IDH1 desregulates the differentiation property of human mesenchymal stem cells through gene-specific epigenetic modification (2015)
  • Author(s): Toguchida J, Jin Y, Watanabe M, Okamoto T
  • Organizer: 第20回CTOS
  • Place of Presentation: Salt Lake City（USA）
  • Year and Date: 2015-11-05
  • Int'l Joint Research
• [Presentation] SS18-SSX, the oncogenic fusion protein in synvival sarcoma, is a cellular context-dependent epigenetic modifier (2015)
  • Author(s): Tamaki S, Fukuta M, Sekiguchi K, Hayakawa K, Jin Y, Hineno S, Okamoto T, Watanbe M, Woltjen K, Ikeya M, Kato T, Toguchida J
  • Organizer: 第20回CTOS
  • Place of Presentation: Salt Lake City（USA）
  • Year and Date: 2015-11-05
  • Int'l Joint Research
• [Presentation] 間葉系幹細胞の骨軟骨分化能における変異型IDH1の影響 (2015)
  • Author(s): 岡本健、金永輝、玉置さくら、松田秀一、戸口田淳也
  • Organizer: 第53回日本癌治療学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2015-10-31
• [Presentation] 細胞初期化技術を用いた肉腫発生メカニズム解析 (2015)
  • Author(s): 河村真吾、秋山治彦、大野貴敏、山田一成、戸口田淳也、山田泰広
  • Organizer: 第30回日本整形外科学会基礎学術集会
  • Place of Presentation: 富山国際会議場（富山県富山市）
  • Year and Date: 2015-10-23
• [Presentation] 変異型IDH1は骨・軟骨関連遺伝子のヒストンを遺伝子特異的に修飾し、間葉系幹細胞の分化能を脱制御する (2015)
  • Author(s): 金永輝、Hassan Elalaf、渡辺真、玉置さくら、日根野翔、松永一仁、Knut Woltjen、岡本健、松田秀一、戸口田淳也
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-10
• [Presentation] 軟骨肉腫の全ゲノム解析 (2015)
  • Author(s): 十時泰、吉田朗彦、細田文恵、中村浩美、濱奈津子、小倉浩一、新井康仁、戸口田淳也、川井章、柴田龍弘
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] iPS細胞技術の肉腫研究への応用 (2015)
  • Author(s): 戸口田淳也
  • Organizer: 第48回日本整形外科学会骨軟部腫瘍学術集会
  • Place of Presentation: かがわ国際会議場（香川県高松市）
  • Year and Date: 2015-07-10
  • Invited
• [Presentation] 間葉系幹細胞の骨分化能における変異型IDH1の影響 (2015)
  • Author(s): 金永輝、Hassan Elalaf、渡辺真、玉置さくら、日根野翔、松永一仁、Knut Woltjen、岡本健、松田秀一、戸口田淳也
  • Organizer: 第48回日本整形外科学会骨軟部腫瘍学術集会
  • Place of Presentation: かがわ国際会議場（香川県高松市）
  • Year and Date: 2015-07-09
• [Presentation] BCOR-CCNB3融合遺伝子陽性のEwing-like sarcomaの治療経験 (2015)
  • Author(s): 朴憲之、岡本健、仲俣岳晴、中山富貴、松田秀一、戸口田淳也
  • Organizer: 第48回日本整形外科学会骨軟部腫瘍学術集会
  • Place of Presentation: かがわ国際会議場（香川県高松市）
  • Year and Date: 2015-07-09