Elucidation of the pathogenesis of HTLV-1-related diseases and exploration of new therapeutic strategies using genetically engineered mice

• Project/Area Number: 17K09931
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Miyazaki
• Principal Investigator: Kameda Takuro 宮崎大学, 医学部, 助教 (30468029)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ATLL / HBZ / CARD11 / 癌 / シグナル伝達 / ウイルス / PRKCb

Outline of Final Research Achievements

We created and analyzed mouse models of adult T-cell leukemia/lymphoma caused by human T-cell leukemia virus (HTLV-1). HBZ transgenic mice (HBZ-Tg) showed chronic inflammation and lymphadenopathy in about 10% of mice by 48 weeks of age. In mice transduced with a driver mutation, CARD11E626K, about 50% of the mice showed lymphadenopathy at 24 weeks of age. In mice with both HBZ and CARD11E626K, about 70% of the mice showed lymphadenopathy at 24 weeks of age. They also showed infiltration of T-cells into various organs and shortened survival. Based on these models, researches on the pathogenesis of ATL and the novel therapies targeting the driver mutation are ongoing.

Academic Significance and Societal Importance of the Research Achievements

世界では3000万人以上のHTLV-1キャリアが存在すると推定されている。日本国内ではHTLV-1キャリアが約100万人存在し、毎年約1100人がATLを発症している。欧米では日本以上にATL は希少であるため、日本にはATLの基礎研究と治療法開発を遂行する責務がある。本研究でATLの遺伝学的基盤を踏まえて作成されたマウスモデルは、今後の新規治療の開発基盤になりうる成果である。

Research Products

• [Journal Article] Novel PRMT5-mediated arginine methylations of HSP90A are essential for maintenance of HSP90A function in NDRG2low ATL and various cancer cells. (2020)
  • Author(s): Ichikawa T, Shanab O, Nakahata S, Shimosaki S, Manachai N, Ono M, Iha H, Shimoda K, Morishita K
  • Journal Title: Biochim Biophys Acta Mol Cell Res Volume: 1867 Issue: 2 Pages: 118615-118615
  • DOI: 10.1016/j.bbamcr.2019.118615
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical significance of soluble CADM1 as a novel marker for adult T-cell leukemia/lymphoma. (2020)
  • Author(s): Nakahata S, Syahrul C, Nakatake A, Sakamoto K, Yoshihama M, Nishikata I, Ukai Y, Matsuura T, Kameda T, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Ito A, Takemoto S, Nakano N, Saito M, Iwanaga M, Sagara Y, Mochida K, Amano M, Maeda K, Sueoka E, Okayama A, Utsunomiya A, Shimoda K, Watanabe T, Morishita K.
  • Journal Title: Haematologica Volume: 105 Issue: 2 Pages: 1-1
  • DOI: 10.3324/haematol.2019.234096
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Degradation of p47 by autophagy contributes to CADM1 overexpression in ATLL cells through the activation of NF-κB. (2019)
  • Author(s): Sarkar B, Nishikata I, Nakahata S, Ichikawa T, Shiraga T, Saha HR, Fujii M, Tanaka Y, Shimoda K, Morishita K.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 3491-3491
  • DOI: 10.1038/s41598-019-39424-7
  • NAID: 120006825908
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling (2019)
  • Author(s): Watatani Yosaku,Ogawa Seishi., et al.
  • Journal Title: Leukemia Volume: 33 Issue: 12 Pages: 2867-2883
  • DOI: 10.1038/s41375-019-0473-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The regulation of NDRG2 expression during ATLL development after HTLV-1 infection. (2019)
  • Author(s): Ichikawa T, Nakahata S, Fujii M, Iha H, Shimoda K, Morishita K.
  • Journal Title: Biochim Biophys Acta Mol Basis Dis Volume: 1865 Issue: 10 Pages: 2633-2646
  • DOI: 10.1016/j.bbadis.2019.07.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical features and treatment outcomes of opportunistic infections among human T-lymphotrophic virus type 1 (HTLV-1) carriers and patients with adult T-cell leukemia-lymphoma (ATL) at a single institution from 2006 to 2016 (2019)
  • Author(s): Kawano Noriaki、Nagahiro Yuri、Yoshida Shuro、Tahara Yoshihiro、Himeji Daisuke、Kuriyama Takuro、Tochigi Taro、Nakaike Takashi、Shimokawa Tomonori、Yamashita Kiyoshi、Ochiai Hidenobu、Marutsuka Kouske、Mashiba Koichi、Shimoda Kazuya、Teshima Takanori、Kikuchi Ikuo
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 59 Issue: 4 Pages: 156-167
  • DOI: 10.3960/jslrt.18032
  • NAID: 130007771348
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access
• [Journal Article] Outcome of allogeneic hematopoietic cell transplantation in patients with adult T-cell leukemia (2018)
  • Author(s): Kamiunten Ayako、Sekine Masaaki、Kameda Takuro、Akizuki Keiichi、Tahira Yuki、Shide Kotaro、Shimoda Haruko、Kato Koji、Hidaka Tomonori、Kubuki Yoko、Shimoda Kazuya
  • Journal Title: Hematological Oncology Volume: 36 Issue: 4 Pages: 651-655
  • DOI: 10.1002/hon.2549
  • Peer Reviewed / Open Access
• [Journal Article] Effects of mogamulizumab in adult T-cell leukemia/lymphoma in clinical practice. (2017)
  • Author(s): Sekine M, Kubuki Y, Kameda T, Takeuchi M, Toyama T, Kawano N, Maeda K, Sato S, Ishizaki J, Kawano H, Kamiunten A, Akizuki K, Tahira Y, Shimoda H, Shide K, Hidaka T, Kitanaka A, Yamashita K, Matsuoka H, Shimoda K
  • Journal Title: European journal of haematology. Volume: 98 Issue: 5 Pages: 501-507
  • DOI: 10.1111/ejh.12863
  • 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
• [Presentation] 成人T細胞白血病・リンパ腫(ATL)最適化医療の確立と、ハイリスクキャリアの同定 (2020)
  • Author(s): 下田和哉
  • Organizer: HTLV-1関連疾患研究領域 研究班合同発表会
• [Presentation] 成人T細胞白血病・リンパ腫(ATL)最適化医療の確立とハイリスクキャリアの同定にむけて (2020)
  • Author(s): 亀田拓郎,下田和哉, 幣光太郎, 上運天綾子, 小川誠司, 片岡圭亮, 柴田龍弘, 宇都宮與, 日高道弘, 北中 明
  • Organizer: 令和元年度第2回班会議報告
• [Presentation] ATL-PDXモデルを用いたバイオマーカーの検討 (2019)
  • Author(s): 上運天綾子，片岡圭亮，亀田拓郎，幣光太郎，田平優貴，関根雅明，秋月渓一，日高智徳，久冨木庸子，小川誠司，下田和哉
  • Organizer: 第6回日本HTLV-1学会学術集会
• [Presentation] 臨床情報とゲノム情報を統合した予後予測モデルによる予後良好aggressive ATL抽出の試み (2019)
  • Author(s): 亀田拓郎，片岡圭亮，三好寛明，幣光太郎，北中明，日高道弘，宇都宮與，柴田龍弘，十時泰，大島孝一，小川誠司，下田和哉
  • Organizer: 第6回日本HTLV-1学会学術集会
• [Presentation] 成人Ｔ細胞白血病リンパ腫に対する新規テーラーメイド治療の確立 (2019)
  • Author(s): 森下大輔，赤沼朋子，平山孝治，水谷明生，戸崎浩和，有川泰由，杉山緑，亀田拓郎，上運天綾子，片岡圭亮，依田成玄，越智陽太郎，幣光太郎，下田和哉，三宅洋，小川誠司
  • Organizer: 第6回日本HTLV-1学会学術集会
• [Presentation] 宮崎県内におけるATLの現状について (2019)
  • Author(s): 関根雅明，田平優貴，秋月渓一，上運天綾子，亀田拓郎，幣光太郎，日髙智徳，久冨木庸子，下田和哉
  • Organizer: 第6回日本HTLV-1学会学術集会
• [Presentation] 成人T細胞性白血病治療の現状と近未来 (2019)
  • Author(s): 下田和哉
  • Organizer: 第6回日本HTLV-1学会学術集会
• [Presentation] ATL in Miyazaki Prefecture (2019)
  • Author(s): Masaaki Sekine, Yuki Tahira, Keiichi Akizuki, Ayako Kamiunten, Takuro Kameda, Kotaro Shide, Tomonori Hidaka, Yoko Kubuki, Kazuya Shimoda
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 成人T細胞白血病・リンパ腫(ATL)最適化医療の確立とハイリスクキャリアの同定にむけて (2019)
  • Author(s): 亀田拓郎,下田和哉, 幣光太郎, 上運天綾子, 小川誠司, 片岡圭亮, 柴田龍弘, 宇都宮與, 日高道弘, 北中 明
  • Organizer: 令和元年度第1回班会議報告
• [Presentation] 成人T細胞白血病・リンパ腫(ATL)最適化医療の確立とハイリスクキャリアの同定にむけて (2019)
  • Author(s): 下田和哉, 幣光太郎, 亀田拓郎, 上運天綾子, 片岡圭亮, 小川誠司, 柴田龍弘, 十時泰, 日高道弘, 宇都宮與
  • Organizer: 平成30年度第2回班会議報告
• [Presentation] ATL移植症例における遺伝子異常の臨床的意義の検討 (2019)
  • Author(s): 下田和哉, 幣光太郎, 亀田拓郎, 上運天綾子, 片岡圭亮, 小川誠司, 柴田龍弘, 十時泰, 日高道弘, 宇都宮與
  • Organizer: 平成30年度第2回班会議報告
• [Presentation] 成人T細胞白血病・リンパ腫(ATL)最適化医療の確立と、ハイリスクキャリアの同定 (2019)
  • Author(s): 亀田拓郎,下田和哉
  • Organizer: HTLV-1 関連疾患研究領域 研究班合同発表会
• [Presentation] マウスモデルを用いたATLLにおけるTET2欠損の役割の検討 (2018)
  • Author(s): 亀田拓郎, 幣光太郎, 上運天綾子, 大園芳範, 関根雅明, 田平優貴, 秋月渓一, 日髙智徳, 久冨木庸子, 北中明, 下田和哉
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] 臨床情報とゲノム情報を統合したaggressive ATLの予後予測 (2018)
  • Author(s): 亀田拓郎, 片岡圭亮, 三好寛明, 幣光太郎, 北中明, 日高道弘, 宇都宮與, 柴田龍弘, 大島孝一, 川誠司, 下田和哉
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] High efficacy of anti-TFR1 antibody against the growth of mogamulizmab-resistant ATLL cells. (2018)
  • Author(s): Nakahata S, Shimosaki S, Ichikawa T, Kameda T, Hidaka T, Kubuki Y, Kurosawa G, Shimoda K, Morishita K
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 成人T細胞白血病・リンパ腫(ATL)最適化医療の確立とハイリスクキャリアの同定にむけて (2018)
  • Author(s): 下田和哉, 幣光太郎, 亀田拓郎, 上運天綾子, 片岡圭亮, 小川誠司, 柴田龍弘, 十時泰, 日高道弘, 宇都宮與
  • Organizer: 平成30年度第1回班会議報告
• [Presentation] TET2 Mutation Associated with Organ Infiltrations in ATLL (2018)
  • Author(s): Kameda T, Shide K, Kamiunten A, Tahira Y, Akizuki K, Sekine M, Hidaka T, Kubuki Y, Hidaka M, Utsunomiya A, Ohshima T, Kataoka K, Ogawa S, Shimoda K
  • Organizer: 60th ASH Annual Meeting and Exposition.
  • Int'l Joint Research
• [Presentation] HBZ/PRKCb変異/TET2欠損の多重異常によるATLLマウスモデル作成の試み (2017)
  • Author(s): 亀田拓郎、幣光太郎、上運天綾子、大園芳範、関根雅明、田平優貴、秋月渓一、下田晴子、日髙智徳、久冨木庸子、北中明、下田和哉
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] Effect of HBZ and PRKCbD427N in ATLL development. (2017)
  • Author(s): Takuro Kameda,Kotaro Shide, Masaaki Sekine, Ayako Kamiunten, Yuki Tahira, Keiichi Akizuki, Haruko Shimoda, Tomonori Hidaka, Yoko Kubuki, Kazuya Shimoda
  • Organizer: 第79回日本血液学会学術集会
• [Book] 血液専門医テキスト（改訂第3版） その他の骨髄増殖性疾患 (2019)
  • Author(s): 亀田拓郎、下田和哉
  • Total Pages: 660
  • Publisher: 南江堂
  • ISBN: 9784524248827