Integrated approach toward angioimmunoblastic T-cell lymphoma - elucidation of molecular mechanism and development of diagnostics and therapeutics

• Project/Area Number: 16H02660
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Tsukuba
• Principal Investigator: Chiba Shigeru 筑波大学, 医学医療系, 教授 (60212049)
• Research Collaborator: Kato Takayasu ; Nguyen Bich Tran ; Hattori Keichiro ; Fujisawa Manabu ; Fukumoto Kota ; Tanzima Nuhat Sharna
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥47,450,000 (Direct Cost: ¥36,500,000、Indirect Cost: ¥10,950,000); Fiscal Year 2018: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000); Fiscal Year 2017: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000); Fiscal Year 2016: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000)
• Keywords: 血管免疫芽球性T細胞リンパ腫 / RHOA / TET2 / VAV1 / 治療標的 / がん / ゲノム / シグナル伝達 / 血液がん / 悪性リンパ腫 / 癌 / 遺伝子

Outline of Final Research Achievements

We screened a protein that specifically bound to a previously identified angioimmunoblastic T-cell lymphoma (AITL)-specific RHOA(G17V) mutant, and identified VAV1, a signaling protein. By the binding, VAV1 tyrosine phosphorylation was enhanced and T cell receptor downstream signaling was strengthened. We then showed that dasatinib, a commercially available tyrosine kinase inhibitor, suppressed VAV1 phosphorylation and T cell receptor downstream signals. We also observed that Tet2 gene disruption and RHOA(G17V) expression, mimicking the AITL genome, developed AITL-like T-cell lymphoma in mice, and this tumor responded to dasatinib. The survival of the tumor-bearing recipient mice was prolonged by dasatinib administration.

Academic Significance and Societal Importance of the Research Achievements

研究代表者らが世界的に高い競争力をもつ血管免疫芽球性T細胞リンパ腫(AITL)について、病態解明と診断・治療法開発を目指した。遺伝子変異の同定に基づいて申請した診断法特許が2018年に成立し検査会社が商品化した。一方、変異蛋白質に特異的に結合する蛋白質の同定を手がかりに、この蛋白質をリン酸化する酵素が治療標的になることを見出し、マウスで作製したAITLモデルを用いて、市販されているチロシンキナーゼ阻害剤が有効であることを示した。この成果に基づいて臨床試験を計画している。期待通りの結果が得られれば、既存薬の適応拡大に繋がり、AITLの新規治療薬として大きな意義をもつ。

Research Products

• [Int'l Joint Research] Hopital Henri Mondor/insert U1170 Institut Gustave Roussy(フランス)
• [Int'l Joint Research] University of California, irvine/Stanford University(米国)
• [Int'l Joint Research] Universite Paris-Est/Hopital Henri Mondor(フランス)
• [Int'l Joint Research] University of Medicine and Pharmacy(ベトナム)
• [Journal Article] Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma (2018)
  • Author(s): Hattori Keiichiro、Sakata-Yanagimoto Mamiko、Kusakabe Manabu、Nanmoku Toru、Suehara Yasuhito、Matsuoka Ryota、Noguchi Masayuki、Yokoyama Yasuhisa、Kato Takayasu、Kurita Naoki、Nishikii Hidekazu、Obara Naoshi、Takano Shingo、Ishikawa Eiichi、Matsumura Akira、Muratani Masafumi、Hasegawa Yuichi、Chiba Shigeru
  • Journal Title: Cancer Science Volume: 110 Issue: 1 Pages: 401-407
  • DOI: 10.1111/cas.13848
  • NAID: 120007128280
  • Peer Reviewed / Open Access
• [Journal Article] Droplet digital PCR assay and PNA-LNA clamp method for RHOA mutation detection in angioimmunoblastic T-cell lymphoma (2018)
  • Author(s): Tanzima Nuhat S, Sakata-Yanagimoto M, Komori D, Hattori K, Suehara Y, Fukumoto K, Fujisawa M, Kusakabe M, Matsue K, Wakamatsu H, Shimadzu M, Chiba S
  • Journal Title: Cancer Sci Volume: - Issue: 5 Pages: 1682-1689
  • DOI: 10.1111/cas.13557
  • Peer Reviewed / Open Access
• [Journal Article] Liquid biopsy for the identification of intravascular large B-cell lymphoma (2018)
  • Author(s): Suehara Yasuhito、Sakata-Yanagimoto Mamiko、et al
  • Journal Title: Hematologica Volume: in press Issue: 6 Pages: e241-e244
  • DOI: 10.3324/haematol.2017.178830
  • Peer Reviewed / Open Access
• [Journal Article] BCL6 locus is hypermethylated in angioimmunoblastic T-cell lymphoma. (2017)
  • Author(s): Nishizawa S, Sakata-Yanagimoto M, Hattori K, Muto H, Nguyen T, Izutsu K, Yoshida K, Ogawa S, Nakamura N, Chiba S.
  • Journal Title: Int J Hematol. Volume: - Issue: 4 Pages: 465-469
  • DOI: 10.1007/s12185-016-2159-z
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Detection of the circulating tumor DNAs in angioimmunoblastic T- cell lymphoma (2017)
  • Author(s): Sakata-Yanagimoto Mamiko、Nakamoto-Matsubara Rie、Komori Daisuke、Nguyen Tran B.、Hattori Keiichiro、Nanmoku Toru、Kato Takayasu、Kurita Naoki、Yokoyama Yasuhisa、Obara Naoshi、Hasegawa Yuichi、Shinagawa Atsushi、Chiba Shigeru
  • Journal Title: Annals of hematology Volume: 96 Issue: 9 Pages: 1471-1475
  • DOI: 10.1007/s00277-017-3038-2
  • Peer Reviewed / Open Access
• [Journal Article] Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma (2017)
  • Author(s): Fujisawa M., Sakata-Yanagimoto M., Nishizawa S., Komori D., Gershon P., Kiryu M., Tanzima S., Fukumoto K., Enami T., Muratani M., Yoshida K., Ogawa S., Matsue K., Nakamura N., Takeuchi K., Izutsu K., Fujimoto K., Teshima T., Miyoshi H., Gaulard P., Ohshima K., Chiba S.
  • Journal Title: Leukemia Volume: 32 Issue: 3 Pages: 694-702
  • DOI: 10.1038/leu.2017.273
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A review of the biologic and clinical significance of genetic mutations in angioimmunoblastic T-cell lymphoma (2017)
  • Author(s): Fukumoto K、Nguyen TB、Chiba S、Sakata-Yanagimoto M
  • Journal Title: Cancer Sci Volume: 109 Issue: 3 Pages: 490-496
  • DOI: 10.1111/cas.13393
  • NAID: 120007134344
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of disease-specific MYD88 mutations in circulating DNA in primary central nervous system lymphoma (2017)
  • Author(s): Hattori Keiichiro、Sakata-Yanagimoto Mamiko、Suehara Yasuhito、Yokoyama Yasuhisa、Kato Takayasu、Kurita Naoki、Nishikii Hidekazu、Obara Naoshi、Takano Shingo、Ishikawa Eiichi、Matsumura Akira、Hasegawa Yuichi、Chiba Shigeru
  • Journal Title: Cancer science Volume: 109 Issue: 1 Pages: 225-230
  • DOI: 10.1111/cas.13450
  • NAID: 120007134545
  • Peer Reviewed / Open Access
• [Journal Article] Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma (2017)
  • Author(s): Fujisawa M, Chiba S, Sakata-Yanagimoto M
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 57 Issue: 3 Pages: 109-119
  • DOI: 10.3960/jslrt.17019
  • NAID: 130006286291
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access
• [Journal Article] Identification of cell-type-specific mutations in nodal T-cell lymphomas. (2017)
  • Author(s): Nguyen TB, Sakata-Yanagimoto M, Asabe Y, Matsubara D, Kano J, Yoshida K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Izutsu K, Nakamura N, Takeuchi K, Miyoshi H, Ohshima K, Minowa T, Ogawa S, Noguchi M, Chiba S.
  • Journal Title: Blood Cancer Journal Volume: 7 Issue: 1 Pages: e516-e516
  • DOI: 10.1038/bcj.2016.122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ynamics of clonal evolution in myelodysplastic syndromes. (2017)
  • Author(s): Makishima H, et al.
  • Journal Title: Nat Genet. Volume: 49 Issue: 2 Pages: 204-212
  • DOI: 10.1038/ng.3742
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Dysregulation of TET2 in hematologic malignancies. (2017)
  • Author(s): Chiba S.
  • Journal Title: International Journal of Hematology Volume: 105 Issue: 1 Pages: 17-21
  • DOI: 10.1007/s12185-016-2122-z
  • Peer Reviewed / Open Access
• [Journal Article] MYD88 (L265P) mutation is associated with an unfavourable outcome of primary central nervous system lymphoma. (2016)
  • Author(s): Hattori K, Sakata-Yanagimoto M, Okoshi Y, Goshima Y, Yanagimoto S, Nakamoto-Matsubara R, Sato T, Noguchi M, Takano S, Ishikawa E, Yamamoto T, Matsumura A, Chiba S.
  • Journal Title: Br J Haematol Volume: - Issue: 3 Pages: 492-494
  • DOI: 10.1111/bjh.14080
  • Peer Reviewed / Open Access
• [Journal Article] DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft versus host disease. (2016)
  • Author(s): Nishikii H, Kim BS, Yokoyama Y, Chen Y, Baker J, Pierini A, Alvarez M, Mavers M, Maas-Bauer K, Pan Y, Chiba S, Negrin RS.
  • Journal Title: Blood Volume: 128 Issue: 24 Pages: 2846-2858
  • DOI: 10.1182/blood-2016-06-723783
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinicopathologic analysis of angioimmunoblastic T-cell lymphoma with or without RHOA G17V mutation using formalin-fixed paraffin-embedded sections. (2016)
  • Author(s): Nagao R, Kikuti YY, Carreras J, Kikuchi T, Miyaoka M, Matsushita H, Kojima M, Ando K, Sakata-Yanagimoto M, Chiba S, Nakamura N.
  • Journal Title: Am J Surg Pathol Volume: 40 Issue: 8 Pages: 1041-50
  • DOI: 10.1097/pas.0000000000000651
  • Peer Reviewed / Int'l Joint Research
• [Presentation] TP53 mutations found in the serum of malignant lymphoma patients at remission derive from clonal hematopoiesis rather than minimal residual disease. (2018)
  • Author(s): Yasuhito Suehara, Mamiko Sakata-Yanagimoto, Keiichiro Hattori, Taiki Sato, Masayuki Noguchi, Tatsuhiro Sakamoto, Manabu Kusakabe, Naoki Kurita, Takayasu Kato, Yasuhisa Yokoyama, Hidekazu Nishikii, Naoshi Obara, Yuichi Hasegawa, Shigeru Chiba
  • Organizer: 2018 ASH Meeting on Lymphoma Biology
  • Int'l Joint Research
• [Presentation] Effectiveness of Dasatinib in an Angioimmunoblastic T-Cell Lymphoma Mouse Model (2018)
  • Author(s): Tran B. Nguyen, Mamiko Sakata-Yanagimoto, Manabu Fujisawa, Shigeru Chiba
  • Organizer: The 9th JSH International Symposium
  • Int'l Joint Research
• [Presentation] Droplet digital PCR and PNA-LNA clamp method for RHOA mutation detection in peripheral T-cell lymphoma (2018)
  • Author(s): Sharna Tanzima nuhat, 坂田（柳元）麻実子，小森大輔，服部圭一朗，福本浩太，藤澤 学，末永孝生，若松宏武，島津光伸，千葉 滋
  • Organizer: 第58回 日本リンパ網内系学会総会
• [Presentation] Liquid biopsy for the identification of intravascular large B-cell lymphoma (2018)
  • Author(s): 末原 泰人, 坂田（柳元）麻実子，服部圭一朗，伊藤孝美，梶 大介，山本 豪，末永孝生，佐藤泰樹，野口雅之，千葉 滋
  • Organizer: 第58回 日本リンパ網内系学会総会
• [Presentation] Genetic evidence implying the common precursor cells for primary and extra-central nervous system relapsed tumors in primary central nervous system lymphoma (2018)
  • Author(s): Keiichiro Hattori, Mamiko Sakata-Yanagimoto, Tohru Nanmoku, Yasuhito Suehara, Ryota Matsuoka, Masayuki Noguchi, Yasuhisa Yokoyama, Takayasu Kato, Naoki Kurita, Hidekazu Nishikii, Naoshi Obara, Shingo Takano, Eiichi Ishikawa, Akira Matsumura, Masafumi Muratani, Yuichi Hasegawa, Shigeru Chiba
  • Organizer: 23rd Congress of EHA
  • Int'l Joint Research
• [Presentation] New waves in graft-versus-host disease control: information posted from Japan (2018)
  • Author(s): Shigeru Chiba
  • Organizer: 9th Asian Cellular Therapy Organization Meeting
  • Int'l Joint Research / Invited
• [Presentation] Mechanisms of lymphomagenesis by mutant RHOA. (2017)
  • Author(s): Shigeru Chiba.
  • Organizer: 2017 US-Japan Symposium on Normal/Malignant Hematopoiesis and Novel Therapies for Hematologic Malignancies
  • Place of Presentation: Hilton Waikoloa Village, Waikoloa, HI, USA
  • Year and Date: 2017-02-21
  • Int'l Joint Research / Invited
• [Presentation] Activation of RHOA-VAV1 Signaling Axis in Angioimmunoblastic T-Cell Lymphoma (2017)
  • Author(s): Manabu Fujisawa, Mamiko Sakata-Yanagimoto, Shoko Nishizawa, Shigeru Chiba
  • Organizer: 22nd Congress of European Hematology Association 2017
  • Int'l Joint Research
• [Presentation] A novel function of the G17V RHOA mutant in angioimmunoblastic T- cell lymphoma (2017)
  • Author(s): 坂田（柳元）麻実子，藤澤 学，Ngyuen Bich Tran，千葉 滋
  • Organizer: 第76回日本癌学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] Clonal hematopoiesis as an origin of myeloid and lymphoid cancers (2017)
  • Author(s): 千葉 滋
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] Combination of Tet2 loss-of-function and RHOAG17V expression leads to T-cell lymphoma in mice (2017)
  • Author(s): Nguyen Bich Tran，Mamiko Sakata-Yanagimoto，Manabu Fujisawa，Shigeru Chiba
  • Organizer: 第79回日本血液学会学術集会
  • Int'l Joint Research
• [Presentation] Targeting T-Cell Receptor Signaling Pathway in Angioimmunoblastic T-Cell Lymphoma (2017)
  • Author(s): Nguyen Bich Tran，Mamiko Sakata-Yanagimoto，Manabu Fujisawa，Shigeru Chiba
  • Organizer: The American Society of Hematology 59th Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Recurrent VAV1 Abnormalities in Angioimmunoblastic T Cell Lymphoma. (2016)
  • Author(s): Daisuke Komori, Mamiko Sakata-Yanagimoto, Sharna Tanzima Nuhat, Kota Fukumoto, Manabu Fujisawa, Shoko Nishizawa, Kosei Matsue, Koji Izutsu, Naoya Nakamura, Kenichi Yoshida, Seishi Ogawa, Shigeru Chiba.
  • Organizer: The American Society of Hematology 58th Annual Meeting and Exposition
  • Place of Presentation: San Diego Convention Center, San Diego, CA, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] 多段階的遺伝子変異獲得による血液がんの発症メカニズム. (2016)
  • Author(s): 坂田（柳元）麻実子，真家紘一郎，Nguyen Tran，千葉 滋.
  • 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
  • Invited
• [Presentation] Combined loss of Tet2 and Tet3 induces AML sensitive to hypomethylating agents. (2016)
  • Author(s): Koichiro Maie, Mamiko Sakata-Yanagimoto, Motohiko Oshima, Takayasu Kato, Hideharu Muto, Enguerran Mouly, Olivier A. Bernard, Haruhiko Koseki, Atsushi Iwama, Shigeru Chiba.
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜・神奈川県横浜市
  • Year and Date: 2016-10-13
• [Presentation] 血液がんの起源と進展のメカニズム. (2016)
  • Author(s): 坂田（柳元）麻実子，千葉 滋.
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜・神奈川県横浜市
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] TET2 mutations: a predisposing factor for myeloid and T-cell malignancies (2016)
  • Author(s): Mamiko Sakata-Yanagimoto, Koichiro Maie, Bich Tran Nguyen, Shigeru Chiba.
  • Organizer: 第76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
  • Invited
• [Presentation] Integrity of TET dioxygenase activity determines leukemic transformation (2016)
  • Author(s): Koichiro Maie, Mamiko Sakata-Yanagimoto, Motohiko Oshima, Yaeko Nakajima, Hirotaka Matsui, Takayasu Kato, Hideharu Muto, Haruhiko Koseki, Atsushi Iwama, Shigeru Chiba.
  • Organizer: 第76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] Unveiling the molecular pathogenesis of Angioimmunoblastic T-cell lymphoma using laser microdissection based sequencing. (2016)
  • Author(s): Tran B. Nguyen坂田（柳元）麻実子，千葉 滋浅部幸成，坂田（柳元）麻実子，千葉 滋.
  • Organizer: 第56回 日本リンパ網内系学会総会
  • Place of Presentation: ホテル日航熊本・熊本県熊本市
  • Year and Date: 2016-09-01
  • Int'l Joint Research
• [Presentation] Aging and TET Dioxygenases in Leukemo/lymphomagenesis. (2016)
  • Author(s): Shigeru Chiba.
  • Organizer: The 5th JCA-AACR Special Joint Conference
  • Place of Presentation: ヒルトン東京ベイ・千葉県浦安市
  • Year and Date: 2016-07-13
  • Int'l Joint Research / Invited
• [Presentation] Combined Loss of Tet2/Tet3 Dioxygenases Induces Acute Myeloid Leukemia Sensitive to Hypomethylating Agents. (2016)
  • Author(s): Koichiro Maie, Mamiko Sakata-Yanagimoto, Motohiko Oshima, Yaeko Nakajima-Takagi, Hirotaka Matsui, Takayasu Kato, Hideharu Muto, Enguerran Mouly, Olivier A Bernard, Haruhiko Koseki, Atsushi Iwama, Shigeru Chiba
  • Organizer: The 5th JCA-AACR Special Joint Conference
  • Place of Presentation: ヒルトン東京ベイ・千葉県浦安市
  • Year and Date: 2016-07-13
  • Int'l Joint Research
• [Presentation] Understanding the Molecular Pathogenesis of Peripheral T-cell Lymphoma by Laser Microdissection-based Sequencing. (2016)
  • Author(s): Tran B. Nguyen, Mamiko Sakata-Yanagimoto, Yukitsugu Asabe, Kenichi Yoshida, Koji Izutsu, Naoya Nakamura, Kengo Takeuchi, Seishi Ogawa, Shigeru Chiba
  • Organizer: The 5th JCA-AACR Special Joint Conference
  • Place of Presentation: ヒルトン東京ベイ・千葉県浦安市
  • Year and Date: 2016-07-13
  • Int'l Joint Research
• [Presentation] Unveiling the Molecular Pathogenesis of Angioimmunoblastic T-cell Lymphoma Using Laser Microdissection Based Sequencing (2016)
  • Author(s): Tran B. Nguyen, Yukitsugu Asabe, Mamiko Sakata-Yanagimoto, Shigeru Chiba
  • Organizer: The 35th Sapporo International Cancer Symposium 2016 Cancer Epigenome: From discovery to translation
  • Place of Presentation: ロイトン札幌・北海道札幌市
  • Year and Date: 2016-06-24
  • Int'l Joint Research
• [Presentation] Double inactivation of tet2 and tet4 induces hypomethylating agent-sensitive acute myeloid leukemia. (2016)
  • Author(s): Koichiro Maie, Mamiko Sakata-Yanagimoto, Motohiko Oshima, Takayasu Kato, Hideharu Muto, Enguerran Mouly, Olivier A Bernard, Haruhiko Koseki, Atsushi Iwama, Shigeru Chiba
  • Organizer: 21th Congress of EHA 2016
  • Place of Presentation: Bella Center, Copenhagen, Denmark
  • Year and Date: 2016-06-09
  • Int'l Joint Research
• [Book] プレシジョン・メディシン ビッグデータの構築・分析から臨床応用・課題まで (2018)
  • Author(s): 千葉 滋、他54名（分担執筆）
  • Total Pages: 373
  • Publisher: エヌ・ティー・エス
  • ISBN: 9784860435806
• [Remarks] 筑波大学血液内科
  • URL: http://www.ketsunai.com
• [Remarks] 筑波大学血液内科
• [Patent(Industrial Property Rights)] VAVファミリーに属する癌原遺伝子タンパク質のリン酸化で同定される腫瘍の治療剤 (2016)
  • Inventor(s): 千葉滋，坂田(柳元)麻実子
  • Industrial Property Rights Holder: 国立大学法人筑波大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-215521
  • Filing Date: 2016-11-02