Analysis of the mechanisms for transient expression of HTLV-1 Tax and development of novel immunotherapy

• Project/Area Number: 17K07166
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kyoto University
• Principal Investigator: Yasunaga Jun-ichirou 京都大学, ウイルス・再生医科学研究所, 講師 (40362404)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HTLV-1 / 癌

Outline of Final Research Achievements

It was found that both transient expression of Tax and continuous expression of HBZ are important for the maintenance of ATL cell lines, such as MT-1 and KK-1. This finding was published PNAS (Mahgoub M, Yasunaga JI, Iwami S, Nakaoka S, Koizumi Y, Shimura K, and Matsuoka M. Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells. Proc Natl Acad Sci USA, 2018. doi: 10.1073/pnas.1715724115). ATAC-seq and ChIP-seq were carried out to see the effect of the transient expression of Tax on the epigenetic status of host cells. Analysis using HBZ transgenic mice showed that IL-10 plays important roles in T-cell proliferation induced by HBZ.

Academic Significance and Societal Importance of the Research Achievements

Taxは強力ながん蛋白質であるが、免疫原性が高いためATL細胞では発現が抑制されており、発がんにおける意義は不明であった。本研究により、Taxの一過性発現とHBZの持続発現の発がんにおける意義を初めて報告した。本研究で得られた知見はHTLV-1の潜伏機構、発がん機構の解明に寄与できると考える。本研究で行ったTaxの発現誘導とTaxワクチンの併用療法の開発をさらに推進することで、ATLの発症予防法、再発予防法の開発に繋がると考える。

Research Products

• [Int'l Joint Research] Imperial College London(英国)
• [Journal Article] IL-7R-Dependent Phosphatidylinositol 3-Kinase Competes with the STAT5 Signal to Modulate T Cell Development and Homeostasis. (2020)
  • Author(s): Cui G, Shimba A, Ma G, Takahara K, Tani-Ichi S, Zhu Y, Asahi T, Abe A, Miyachi H, Kitano S, Hara T, Yasunaga JI, Suwanai H, Yamada H, Matsuoka M, Ueki K, Yoshikai Y, Ikuta K.
  • Journal Title: The Journal of Immunology Volume: 204 Issue: 4 Pages: 844-857
  • DOI: 10.4049/jimmunol.1900456
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IL-2/IL-2 Receptor Pathway Plays a Crucial Role in the Growth and Malignant Transformation of HTLV-1-Infected T Cells to Develop Adult T-Cell Leukemia. (2020)
  • Author(s): Maeda M, Tanabe-Shibuya J, Miyazato P, Masutani H, Yasunaga JI, Usami K, Shimizu A, Matsuoka M.
  • Journal Title: Frontiers in Microbiology Volume: 11 Pages: 356-356
  • DOI: 10.3389/fmicb.2020.00356
  • NAID: 120006936325
  • Peer Reviewed / Open Access
• [Journal Article] Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo (2019)
  • Author(s): Ma Guangyong、Yasunaga Jun-ichirou、Ohshima Koichi、Matsumoto Tadashi、Matsuoka Masao
  • Journal Title: Journal of Virology Volume: 93 Issue: 16
  • DOI: 10.1128/jvi.00413-19
  • Peer Reviewed / Open Access
• [Journal Article] Distinct gene expression signatures induced by viral transactivators of different HTLV-1 subgroups that confer a different risk of HAM/TSP. (2018)
  • Author(s): Naito T, Yasunaga JI, Mitobe Y, Shirai K, Sejima H, Ushirogawa H, Tanaka Y, Nakamura T, Hanada K, Fujii M, Matsuoka M, Saito M.
  • Journal Title: Retrovirology Volume: 15 Issue: 1 Pages: 72-72
  • DOI: 10.1186/s12977-018-0454-x
  • NAID: 120006847301
  • Peer Reviewed / Open Access
• [Journal Article] Long Noncoding RNA ANRIL Supports Proliferation of Adult T-Cell Leukemia Cells through Cooperation with EZH2 (2018)
  • Author(s): Song Zaowen、Wu Wencai、Chen Mengyun、Cheng Wenzhao、Yu Juntao、Fang Jinyong、Xu Lingling、Yasunaga Jun-ichirou、Matsuoka Masao、Zhao Tiejun
  • Journal Title: Journal of Virology Volume: 92 Issue: 24
  • DOI: 10.1128/jvi.00909-18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells. (2018)
  • Author(s): Mahgoub M, Yasunaga JI, Iwami S, Nakaoka S, Koizumi Y, Shimura K, Matsuoka M.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 115 Issue: 6 Pages: 529-538
  • DOI: 10.1073/pnas.1715724115
  • NAID: 120006697286
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo (2017)
  • Author(s): Furuta Rie、Yasunaga Jun-ichirou、Miura Michi、Sugata Kenji、Saito Akatsuki、Akari Hirofumi、Ueno Takaharu、Takenouchi Norihiro、Fujisawa Jun-ichi、Koh Ki-Ryang、Higuchi Yusuke、Mahgoub Mohamed、Shimizu Masakazu、Matsuda Fumihiko、Melamed Anat、Bangham Charles R.、Matsuoka Masao
  • Journal Title: PLOS Pathogens Volume: 13 Issue: 11 Pages: 1-22
  • DOI: 10.1371/journal.ppat.1006722
  • NAID: 120006697285
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oncogenic spiral by infectious pathogens: Cooperation of multiple factors in cancer development (2017)
  • Author(s): Yasunaga Jun-Ichirou、Matsuoka Masao
  • Journal Title: Cancer Science Volume: 109 Issue: 1 Pages: 24-32
  • DOI: 10.1111/cas.13443
  • NAID: 120006460060
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma (2017)
  • Author(s): Kataoka Keisuke、Iwanaga Masako、Yasunaga Jun-ichirou、et al.
  • Journal Title: Blood Volume: 131 Issue: 2 Pages: 215-225
  • DOI: 10.1182/blood-2017-01-761874
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia (2017)
  • Author(s): Takiuchi Yoko、Kobayashi Masayuki、Tada Kohei、Iwai Fumie、Sakurada Maki、Hirabayashi Shigeki、Nagata Kayoko、Shirakawa Kotaro、Shindo Keisuke、Yasunaga Jun-ichirou、Murakawa Yasuhiro、Rajapakse Vinodh、Pommier Yves、Matsuoka Masao、Takaori-Kondo Akifumi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 12849-12849
  • DOI: 10.1038/s41598-017-12924-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Molecular mechanisms for persistent infection and oncogenesis by human T-cell Leukemia virus type 1 (2019)
  • Author(s): Jun-ichirou Yasunaga
  • Organizer: The 18th Awaji International Forum on Infection and Immunity
  • Int'l Joint Research / Invited
• [Presentation] Loss of IL-6 accelerates inflammation and lymphomagenesis in HTLV-1: bZIP factor transgenic mice by modulating Foxp3/IL-10 axis (2019)
  • Author(s): Jun-ichirou Yasunaga, Yusuke Higuchi, Yu Mitagami, Koichi Ohshima, Masao Matsuoka
  • Organizer: 19th International Conference on Human Retrovirology HTLV and Related Viruses
  • Int'l Joint Research
• [Presentation] HTLV-1 Dysregulates IL-6 and IL-10-JAK/STAT Signaling and Induces Leukemia/Lymphoma CD4+T-Cell with Regulatory T-Cell-like Signatures (2019)
  • Author(s): Yusuke Higuchi, Jun-ichirou Yasunaga, Yu Mitagami, Koichi Ohshima, Masao Matsuoka
  • Organizer: The 61st American Society of Hematology Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] 成人T細胞白血病のクロマチン構造解析 (2019)
  • Author(s): 田中 梓、安永 純一朗、藤本 明洋、松岡 雅雄
  • Organizer: 第6回日本HLTV-1学会
• [Presentation] 臨床病態におけるHTLV-1感染細胞クローンの生体内動態 (2019)
  • Author(s): 井崎 幹子、安永 純一朗、松本 美穂、七條 敬文、井上 明威、河北 敏郎、アナート メラメッド、野坂 生郷、末廣 陽子、松岡 雅雄
  • Organizer: 第6回日本HLTV-1学会
• [Presentation] ATLに対する同種造血幹細胞移植におけるHTLV-1プロウイルス配列の臨床的意義 (2019)
  • Author(s): 豊田 康祐、安永 純一朗、崔 日承、末廣 陽子、鵜池 直邦、岡村 純、松岡 雅雄
  • Organizer: 第6回日本HLTV-1学会
• [Presentation] HTLV-1 及びSTLV-1プロウイルス配列の網羅的解析 (2019)
  • Author(s): 七條 敬文、安永 純一朗、大西 知帆、志村 和也、高 起良、竹之内 徳博、佐藤 佳、小柳 義夫、明里 宏文、野坂 生郷、松岡 雅雄
  • Organizer: 第6回日本HLTV-1学会
• [Presentation] Pentosan polysulfate suppresses HTLV-1 transmission and systemic inflammation induced by HBZ (2019)
  • Author(s): 馬 広勇、安永 純一朗、大島 孝一、松本 正、松岡 雅雄
  • Organizer: 第6回日本HLTV-1学会
• [Presentation] 母子感染における抗体価・PVLの動態長期的調査-STLV-1自然感染ニホンザルを用いて- (2019)
  • Author(s): 村田 めぐみ、鷲崎 彩夏、関 洋平、Wei Keat TAN、森本 真弓、兼子 明久、夏目 尊好、鈴木 樹理、安永 純一朗、松岡 雅雄、水上 拓郎、明里 宏文
  • Organizer: 第6回日本HLTV-1学会
• [Presentation] Tax ペプチドパルス樹状細胞療法後の残存ATL 細胞およびTax 特異的CTL のTCR レパトア解析 (2019)
  • Author(s): 長谷川 温彦、飯野 忠史、白土 基明、宇都宮 勇人、大野 博文、北浦 一孝、松谷 隆治、鈴木 隆二、永野 佳子、松岡 雅雄、神奈木 真理、末廣 陽子
  • Organizer: 第6回日本HLTV-1学会
• [Presentation] 大規模検体におけるHLA・HTLV-1プロウイルス量の統合解析におけるHAM/TSP発症リスクの推定 (2019)
  • Author(s): 川口 修治、清水 正和、安永 純一朗、高橋 めい子、岡山 昭彦、山野 嘉久、内丸 薫、研究協力施設 JSPFAD、川上 純、松岡 雅雄、松田 文彦
  • Organizer: 第6回日本HLTV-1学会
• [Presentation] IL-6/IL-10 シグナル経路の撹乱におけるHTLV-1 bZIP factorの病原性発現機構 (2019)
  • Author(s): 樋口悠介、安永純一朗、松岡雅雄
  • Organizer: 第6回日本HLTV-1学会
• [Presentation] レトロウイルスがコードするアンチセンスRNAの核局在はウイルスの持続感染に関与する (2019)
  • Author(s): 安永純一朗、松岡雅雄
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Epigenetic alterations by transient expression of HTLV-1 Tax in ATL cell (2019)
  • Author(s): 栗田大輔、安永純一朗、田中梓、松岡雅雄
  • Organizer: 第81回日本血液学会
• [Presentation] IL-10-JAK-STAT signaling pathway is involved in inflammation and oncogenesis induced by HTLV-1 bZIP factor (2019)
  • Author(s): 樋口悠介、安永純一朗、三田上悠、大島孝一、松岡雅雄
  • Organizer: 第81回日本血液学会
• [Presentation] ヒトT 細胞白血病ウイルス1型の免疫逃避機構と治療戦略 (2018)
  • Author(s): 松岡雅雄、安永純一朗
  • Organizer: 第5回日本HTLV-1学会学術集会
  • Invited
• [Presentation] HTLV-1 及びHTLV-2 キャリアにおけるプロウイルス配列の網羅的解析 (2018)
  • Author(s): 七條敬文、安永純一朗、大西知帆、エドワードマーフィー、松岡雅雄
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] ニホンザルにおける高頻度なSTLV-1 自然感染に関する疫学調査 (2018)
  • Author(s): 村田めぐみ、鷲崎彩夏、関洋平、安永純一朗、松岡雅雄、水上拓郎、明里宏文
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] ATL に対するTax 標的樹状細胞ワクチン療法の5 年追跡調査結果 (2018)
  • Author(s): 宇都宮勇人、飯野忠史、長谷川温彦、大野博文、平田聖子、安永純一朗、松岡雅雄、福田哲也、宇都宮與、赤司浩一、神奈木真理、末廣陽子
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] 抗 CCR4 抗体を併用したTax 標的樹状細胞ワクチン療法における免疫学的解析―第 Ia/Ib 相試験中間解析― (2018)
  • Author(s): 大野博文、長谷川温彦、宇都宮勇人、安永純一朗、松岡雅雄、飯野忠史、白土基明、福田哲也、石田高司、赤司浩一、神奈木真理、末廣陽子
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] HTLV-1 bZIP factor RNAはプロモーター活性依存的に核に局在し、ATL細胞の増殖を促進する (2018)
  • Author(s): 馬広勇、安永純一朗、松岡雅雄
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 間欠的HTLV-1 Tax発現に伴うクロマチン構造およびトラスクリプトーム変化 (2018)
  • Author(s): 栗田大輔、安永純一朗、田中梓、Mahgoub Mohamed、松岡雅雄
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] NUCLEAR RETENTION AND FUNCTIONS OF HTLV-1 AND HIV-1 ANTISENSE RNAS (2018)
  • Author(s): Ma, G., Yasunaga, JI., and Matsuoka, M.
  • Organizer: Nature Conferences, Viral Infection and Immune Response
  • Int'l Joint Research
• [Presentation] ATLに対する同種造血幹細胞移植における欠損型HTLV-1プロウイルスの臨床的意義：ATL-NST試験併合解析結果 (2018)
  • Author(s): 豊田康祐、安永純一朗、崔日承、末廣陽子、鵜池直邦、岡村純、松岡雅雄
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Molecular mechanisms of oncogenesis by human T-cell leukemia virus type 1. (2018)
  • Author(s): Yasunaga, JI.
  • Organizer: The 13th International Symposium of the Institute Network for Biomedical Sciences
  • Int'l Joint Research
• [Presentation] Promoter-mediated nuclear retention of HBZ RNA is involved in proliferation of adult T-cell leukemia (ATL) cells (2018)
  • Author(s): Ma, G., Yasunaga, JI., and Matsuoka, M.
  • Organizer: 25th East Asia Joint Symposium
  • Int'l Joint Research
• [Presentation] Comprehensive analysis of proviral sequences in HTLV-1 and HTLV-2 carriers (2018)
  • Author(s): Shichijo、Jun-ichirou Yasunaga、Kazuya Shimura、Kei Sato、Yoshio Koyanagi、Patrick Green、Edward Murphy、Masao Matsuoka
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Loss of IL-6 accelerates inflammation and lymphomagenesis in HTLV-1 bZIP factor transgenic mice (2018)
  • Author(s): Yusuke Higuchi、Jun-ichirou Yasunaga、Yu Mitagami、Koichi Ohshima、Masao Matsuoka
  • Organizer: 第19回熊本エイズセミナー
  • Int'l Joint Research
• [Presentation] Dynamic Changes of Chromatin Structure and Transcription By Transient Expression of HTLV-1 Tax in ATL Cells (2018)
  • Author(s): Kurita, D., Yasunaga, JI., Tanaka, A., Mahgoub, M., and Matsuoka, M.
  • Organizer: The 60th American Society of Hematology Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Tax-targeting dendritic cell therapy for ATL: A Phase Ia/Ib clinical study (2018)
  • Author(s): Shiratsuchi, M., Fukuda, T., Iino, T., Hasegawa, A., Yasunaga, JI., Watanabe, K., Hirata, A., Utsunomiya, H., Ohno, H., Ishida, T., Akashi, K., Matsuoka, M., Kannagi, M. and Suehrio, Y.
  • Organizer: The 60th American Society of Hematology Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] HTLV-1 Infection in Multiple Lineages of Hematopoietic Cells. (2017)
  • Author(s): Furuta, R.,Yasunaga, JI., Miura, M., Sugata, K., Saito, A., Akari, H., Ueno, T., Takenouchi, N., Fujisawa, J., Kouh, K., Shimizu, M., Matsuda, F., Melamed, A., Bangham, CR., and Matsuoka, M
  • Organizer: 18th Interbational Conference on Human Retrovirology HTLV and Related Viruses
  • Int'l Joint Research
• [Presentation] Transient Tax Expression is Essential for ATL Survival: Insight Based on Single Cell Analysis (2017)
  • Author(s): Mahgoub, M., Yasunaga, JI., Shimura, K., Furuta, R., and Matsuoka, M
  • Organizer: 18th Interbational Conference on Human Retrovirology HTLV and Related Viruses
  • Int'l Joint Research
• [Presentation] HTLV-1 bZIP Factor Promotes T-cell Proliferation by Impairing the Suppressive Function of TIGIT and PD-1 (2017)
  • Author(s): Kinosada, H., Yasunaga, JI. Shimura, K., and Matsuoka, M
  • Organizer: 18th Interbational Conference on Human Retrovirology HTLV and Related Viruses
  • Int'l Joint Research
• [Presentation] HTLV-1 bZIP factorを抗原としたワクチンの開発と霊長類モデルによる効果の検証 (2017)
  • Author(s): 安永純一朗、菅田謙治、三浦未知、明里宏文、松岡雅雄
  • Organizer: 第27回抗ウイルス療法学会学術集会・総会
• [Presentation] HTLV-1による発がん機構 (2017)
  • Author(s): 安永純一朗
  • Organizer: 第20回日本レトロウイルス研究会 夏季セミナー
  • Invited
• [Presentation] HTLV-1がコードする2つのがん遺伝子taxとHTLV-1 bZIP factor の相反する機能と役割 (2017)
  • Author(s): 安永純一朗
  • Organizer: 第4回日本HTLV-1学会学術集会
  • Invited
• [Presentation] HBZ downregulates miR-455, a tumor suppressor microRNA in ATL (2017)
  • Author(s): Ma, G., Yasunaga, JI., Miura, M., Matsumoto, T., Matsuoka, M
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] Characterization of p12, p30 and p13 Accessory Genes Conservation in Simian T-cell Leukemia Virus Type-1 (2017)
  • Author(s): Mahgoub, M. Yasunaga, JI., Tanabe, J., Matsuoka, M
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] IL-6の抑制はHBZによる炎症、発がんを加速する (2017)
  • Author(s): 樋口悠介、安永純一朗、三田上侑生、大島孝一、松岡雅雄
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] 成人T細胞白血病細胞のクロマチン構造解析 (2017)
  • Author(s): 田中梓、安永純一朗、藤本明洋、松岡雅雄
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] HTLV-1 bZIP factorによる c-fos遺伝子発現制御機構 (2017)
  • Author(s): 豊田康祐、安永純一朗、川月章弘、松岡雅雄
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] Transient expression of HTLV-1 Tax is critical event for persistence of adult T-cell leukemia cells (2017)
  • Author(s): Mahgoub, M., Yasunaga, JI., Iwami, S., and Matsuoka,M
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] HTLV-1 bZIP factor suppresses c-fos transcription to hijack cellular signaling pathways (2017)
  • Author(s): Toyoda, K., Yasunaga, JI., Kawatsuki, A., and Matsuoka, M
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] HTLV-1 bZIP factor downregulates miR-455, a tumor suppressor microRNA in ATL (2017)
  • Author(s): Yasunaga, JI., and Matsuoka, M
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Loss of IL-6 accelerates inflammation and lymphomagenesis in HTLV-1 bZIP factor transgenic mice lymphomagenesis in HTLV-1 bZIP factor transgenic mice (2017)
  • Author(s): Higuchi, Y., Yasunaga, J., Mitagami, Y., Ohshima, K., and Matsuoka, M
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Evolutional insight on accessory genes of simian T-cell leukemia virus type 1 (2017)
  • Author(s): Mahgoub, M., Yasunaga, JI., and Matsuoka, M
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] HTLV-1 bZIP factor (HBZ) downregulates miR-455, a tumor suppressor microRNA in HTLV-1 infected cells (2017)
  • Author(s): Ma, G., Yasunaga, JI., and Matsuoka, M
  • Organizer: 第65回日本ウイルス学会学術集会
• [Remarks] ヒトT細胞白血病ウイルス1型（HTLV-1）の新しい感染維持機構を解明
  • URL: http://www.infront.kyoto-u.ac.jp/achievements/post-3010/
• [Remarks] ヒトT細胞白血病ウイルス1型（HTLV－1）の新しい感染維持機構を解明
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2017/180123_1.html
• [Remarks] The fewer the deadlier
  • URL: https://www.kyoto-u.ac.jp/en/research/research_results/2017/180123_1.html