Study for epigenetic abnormality of microRNA in lymphoma biology

• Project/Area Number: 15K06907
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical genome science
• Research Institution: The University of Tokyo
• Principal Investigator: Yamagishi Makoto 東京大学, 大学院新領域創成科学研究科, 特任講師 (90625261)
• Project Period (FY): 2015-10-21 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: microRNA / エピジェネティクス / 悪性リンパ腫 / HTLV-1 / ATL / 遺伝子翻訳 / リンパ腫 / B細胞リンパ腫 / シグナル伝達

Outline of Final Research Achievements

Defenseless signaling is the true nature of the cancer cell. By using RISC-capture assay for normal and clinical samples, this study demonstrates that the signaling cascade habitually confronts epigenetic interference composed of miRNA group in human cells. In malignant lymphoma cells, aberrant action of epigenetic factors hierarchically influences the functional miRNA en masse, enhancing target gene translation and coherent active crosstalk involving NF-kB, Ras-Erk, and Akt-mTOR. We illustrate an example of a biological masterplan comprised of signaling networks, miRNAs, translation regulation, and epigenetic mechanisms. Furthermore, we show that appropriate inhibition of the signaling cascades or the epigenetic abnormality appear to be effective for malignant lymphoma.

Research Products

• [Journal Article] Targeting EZH2 in cancer therapy (2017)
  • Author(s): Yamagishi M, Uchimaru K.
  • Journal Title: Curr Opin Oncol Volume: 29 Issue: 5 Pages: 375-381
  • DOI: 10.1097/cco.0000000000000390
  • Peer Reviewed / Open Access
• [Journal Article] EVI1 modulates oncogenic role of GPC1 in pancreatic carcinogenesis (2017)
  • Author(s): Tanaka Mariko、Ishikawa Shumpei、Ushiku Tetsuo、Morikawa Teppei、Isagawa Takayuki、Yamagishi Makoto、Yamamoto Hiroyuki、Katoh Hiroto、Takeshita Kimiko、Arita Junichi、Sakamoto Yoshihiro、Hasegawa Kiyoshi、Kokudo Norihiro、Fukayama Masashi
  • Journal Title: Oncotarget Volume: 8 Issue: 59 Pages: 99552-99566
  • DOI: 10.18632/oncotarget.20601
  • Peer Reviewed / Open Access
• [Journal Article] 特集 / 成人T細胞白血病リンパ腫(ATL)研究と診療の進歩「ATL発症における遺伝子翻訳異常」 (2017)
  • Author(s): 山岸誠、内丸薫
  • Journal Title: 血液内科 Volume: 74(3) Pages: 314-319
• [Journal Article] Homeostatically Maintained Resting Naive CD4+ T Cells Resist Latent HIV Reactivation. (2016)
  • Author(s): Tsunetsugu-Yokota Y, Kobayahi-Ishihara M, Wada Y, Terahara K, Takeyama H, Kawana-Tachikawa A, Tokunaga K, Yamagishi M, Martinez JP, Meyerhans A.
  • Journal Title: Front. Microbiol. Volume: 7 Pages: 1944-1944
  • DOI: 10.3389/fmicb.2016.01944
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polycomb-dependent epigenetic landscape in adult T-cell leukemia. (2016)
  • Author(s): Dai Fujikawa; Shota Nakagawa; Makoto Hori; Naoya Kurokawa; Ai Soejima; Kazumi Nakano; Tadanori Yamochi; Makoto Nakashima; Seiichiro Kobayashi; Yuetsu Tanaka; Masako Iwanaga; Atae Utsunomiya; Kaoru Uchimaru; Makoto Yamagishi; Toshiki Watanabe
  • Journal Title: Blood Volume: 127 Issue: 14 Pages: 1790-1802
  • DOI: 10.1182/blood-2015-08-662593
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 特集/成人T細胞白血病(ATL)研究の現状「ATL細胞におけるEZH1/2依存的なエピゲノム制御異常」 (2016)
  • Author(s): 山岸誠、渡邉俊樹
  • Journal Title: 血液フロンティア Volume: 26(4) Pages: 35-42
• [Journal Article] Coordinated loss of microRNA group causes defenseless signaling in malignant lymphoma (2015)
  • Author(s): Yamagishi M, Katano H, Hishima T, Shimoyama T, Ota Y, Nakano K, Ishida T, Okada S, Watanabe T.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 17868-17868
  • DOI: 10.1038/srep17868
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] NF-kB and JAK-STAT pathways shape transcription landscape in adult T-cell leukemia-lymphoma. (2018)
  • Author(s): M.Yamagishi, I.Ishizaki, H.Shiga, K.Nakano, D.Fujikawa, S.Kobayashi, et al.
  • Organizer: 10th T-cell lymphoma forum
  • Int'l Joint Research
• [Presentation] Development and Molecular Analysis of Synthetic Lethality by Targeting EZH1/2 in ATL and HTLV-1-infected cells (2017)
  • Author(s): Makoto Yamagishi, Makoto Hori, Dai Fujikawa, Daisuke Honma, Nobuaki Adachi, Takeo Ohsugi, Kazumi Nakano, Makoto Nakashima, Seiichiro Kobayashi, Masako Iwanaga, Atae Utsunomiya, Yuetsu Tanaka, Seiji Okada, Kunihiro Tsukasaki, Kensei Tobinai, Kazushi Araki, Toshiki Watanabe, Kaoru Uchimaru.
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Comparative Transcriptome Analysis of HTLV-1-infected cells and ATL cells (2017)
  • Author(s): Makoto Yamagishi, Kazumi Nakano, Dai Fujikawa, Seiichiro Kobayashi, Natsumi Araya, Tomoo Sato, Naoko Yagishita, Masako Iwanaga, Atae Utsunomiya, Yuetsu Tanaka, Yoshihisa Yamano, Toshiki Watanabe, Kaoru Uchimaru.
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Development and molecular analysis of synthetic lethality by targeting EZH1 and EZH2 in T cell lymphomas (2017)
  • Author(s): Makoto Yamagishi, Makoto Hori, Dai Fujikawa, Daisuke Honma, Nobuaki Adachi, Takeo Ohsugi, Kazumi Nakano, Makoto Nakashima, Seiichiro Kobayashi, Masako Iwanaga, Atae Utsunomiya, Seiji Okada, Kunihiro Tsukasaki, Kensei Tobinai, Kazushi Araki, Toshiki Watanabe, Kaoru Uchimaru
  • Organizer: T-cell Lymphoma Forum 2016
  • Place of Presentation: San Francisco, CA, U.S.A.
  • Year and Date: 2017-01-26
  • Int'l Joint Research
• [Presentation] EZH1/2, SWI/SNF, and MLL2 dependent heterochromatin formation and abnormal transcriptome in hematological malignancies. (2017)
  • Author(s): Makoto Yamagishi, Dai Fujikawa, Makoto Hori, Daisuke Honma, Nobuaki Adachi, Seiichiro Kobayashi, Masako Iwanaga, Atae Utsunomiya, Seiji Okada, Kunihiro Tsukasaki, Kensei Tobinai, Kazushi Araki, Toshiki Watanabe, Kaoru Uchimaru
  • Organizer: 59th ASH Annual Meeting
  • Int'l Joint Research
• [Presentation] Development and molecular analysis of synthetic lethality by targeting EZH1 and EZH2 in malignant lymphomas (2017)
  • Author(s): Makoto Yamagishi, Makoto Hori, Dai Fujikawa, Daisuke Honma, Nobuaki Adachi, Takeo Ohsugi, Kazumi Nakano, Makoto Nakashima, Seiichiro Kobayashi, Masako Iwanaga, Atae Utsunomiya, Seiji Okada, Kunihiro Tsukasaki, Kensei Tobinai, Kazushi Araki, Toshiki Watanabe, Kaoru Uchimaru
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Tumor cell-of-origin and mutation landscape for EZH1/2 targeting precision therapy (2017)
  • Author(s): Makoto Yamagishi, Dai Fujikawa, Makoto Hori, Daisuke Honma, Nobuaki Adachi, Masako Iwanaga, Atae Utsunomiya, Seiji Okada, Kunihiro Tsukasaki, Kensei Tobinai, Kazushi Araki, Toshiki Watanabe, Kaoru Uchimaru
  • Organizer: 第76回日本血液学会学術総会
• [Presentation] HTLV-1感染によるエピジェネティックなNF-kB活性化とその意義 (2017)
  • Author(s): 山岸誠
  • Organizer: 第4回日本HTLV-1学会学術集会
  • Invited
• [Presentation] Development and molecular analysis of synthetic lethality by targeting EZH1 and EZH2 in non-Hodgkin lymphomas (2016)
  • Author(s): Makoto Yamagishi, Makoto Hori, Dai Fujikawa, Daisuke Honma, Nobuaki Adachi, Takeo Ohsugi, Kazumi Nakano, Makoto Nakashima, Seiichiro Kobayashi, Masako Iwanaga, Atae Utsunomiya, Seiji Okada, Kunihiro Tsukasaki, Kensei Tobinai, Kazushi Araki, Toshiki Watanabe, Kaoru Uchimaru
  • Organizer: the 58th ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego, CA, U.S.A.
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Epigenetic landscape in adult T cell leukemia-lymphoma (ATL); proof of concept for targeting EZH1/2 (2016)
  • Author(s): 山岸誠、藤川大、大杉剛生、本間大輔、安達宣明、堀真琴、中川翔太、中野和民、小林誠一郎、田中勇悦、岩永正子、宇都宮與、塚崎邦弘、荒木一司、内丸薫、渡邉俊樹
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2016-10-13
• [Presentation] Epigenetic-basis synthetic lethality for the therapy of adult T cell leukemia-lymphoma (ATL) (2016)
  • Author(s): 山岸誠、藤川大、大杉剛生、本間大輔、安達宣明、堀真琴、中川翔太、中野和民、小林誠一郎、岩永正子、宇都宮與、荒木一司、内丸薫、渡邉俊樹
  • Organizer: 第75回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2016-10-06
• [Presentation] ATLのエピゲノム異常と分子標的治療への展開 (2016)
  • Author(s): 山岸誠
  • Organizer: 第3回日本HTLV-1学会学術集会
  • Place of Presentation: 鹿児島県市町村自治会館、鹿児島
  • Year and Date: 2016-08-26
  • Invited
• [Presentation] 成人T細胞白血病(ATL)の遺伝子翻訳異常とその意義 (2016)
  • Author(s): 山岸誠、澤礼乃、藤川大、堀真琴、中野和民、宇都宮與、渡邉俊樹、内丸薫
  • Organizer: 第3回日本HTLV-1学会学術集会
  • Place of Presentation: 鹿児島県市町村自治会館、鹿児島
  • Year and Date: 2016-08-26
• [Presentation] Polycomb-dependent epigenetic landscape in adult T cell leukemia (ATL); providing proof of concept for targeting EZH1/2 to selectively eliminate the HTLV-1 infected population (2016)
  • Author(s): Yamagishi M, Fujikawa D, Ohsugi T, Honma D, Adachi N, Nakagawa S, Hori M, Kurokawa N, Soejima A, Nakano K, Yamochi T, Nakashima M, Kobayashi S, Tanaka Y, Iwanaga M, Utsunomiya A, Uchimaru K, Tsukasaki K, Araki K, Watanabe T
  • Organizer: T-cell Lymphoma Forum 2016
  • Place of Presentation: San Francisco, CA, U.S.A.
  • Year and Date: 2016-01-28
  • Int'l Joint Research
• [Presentation] Polycomb-Dependent Epigenetic Landscape in Adult T Cell Leukemia (ATL); Providing Proof of Concept for Targeting EZH1/2 to Selectively Eliminate the HTLV-1 Infected Population (2015)
  • Author(s): Yamagishi M, Fujikawa D, Honma D, Adachi N, Nakagawa S, Hori M, Kurokawa N, Soejima A, Nakano K, Yamochi T, Nakashima M, Kobayashi S, Tanaka Y, Iwanaga M, Utsunomiya A, Uchimaru K, Tsukasaki K, Araki K, Watanabe T
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, U.S.A
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Epigenetically Programmed Defenseless Signaling in Malignant Lymphoma (2015)
  • Author(s): Yamagishi M, Katano H, Hishima T, Ota Y, Okada S, Watanabe T
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, U.S.A
  • Year and Date: 2015-12-05
  • Int'l Joint Research