Understanding follicular helper T cell lymphoma focusing on germinal center B cells

• Project/Area Number: 19H03684
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: University of Tsukuba
• Principal Investigator: Chiba Shigeru 筑波大学, 医学医療系, 教授 (60212049)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2019: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 血管免疫芽球性T細胞リンパ腫 / 濾胞ヘルパーT細胞リンパ腫 / TET2 / 胚中心B細胞 / 濾胞性ヘルパーT細胞リンパ腫 / 濾胞性ヘルパーT細胞 / 微小環境 / RHOA / シングルセル・シークエンス

Outline of Research at the Start

血管免疫芽球性T細胞リンパ腫（AITL）等の濾胞性ヘルパーT細胞リンパ腫（TFHL）は，TET2機能喪失変異をもつクローン性造血（CH）細胞を母体として発症すると推察される。本研究では，CH細胞におけるTET2機能不全が腫瘍性TFH細胞の誘導に寄与しつつ，胚中心B細胞様のB細胞産生を促進し，この細胞集団がTET2機能不全とRHOA(G17V)変異の両者を有するTFH細胞と相互作用しながらAITL/TFHL発症に至ることを証明する。一方，再循環する腫瘍細胞・微小環境構成細胞のダイナミクスと臨床経過との関連を示し，薬剤抵抗性に関わるリンパ球再循環パターンの解明などから新規治療法への手がかりを得る。

Outline of Final Research Achievements

Follicular helper T-cell lymphoma is an intractable malignant lymphoma, and thus, there is a great need to develop new therapeutics. In this study, we clarified the significance of TET2 gene abnormalities identified in more than 80% of follicular helper T-cell lymphomas. Specifically, TET2 gene abnormalities occur in hematopoietic stem cells and are also found in non-neoplastic germinal center B cells in addition to the neoplastic T cells. For the development of follicular helper T-cell lymphoma, demonstrated was the importance of interaction between CD40 expressed on germinal center B-cells with CD40 ligand expressed on the follicular helper T cells.

Academic Significance and Societal Importance of the Research Achievements

腫瘍細胞が発現するCD40リガンドと周囲のB細胞が発現するCD40との相互作用が，濾胞性ヘルパーT細胞リンパ腫の発症に重要であることを示した。従って，CD40リガンドとCD40の相互作用を阻害する薬剤が，濾胞性ヘルパーT細胞リンパ腫の治療薬になる可能性がある。CD40リガンドとCD40の相互作用を阻害する薬剤は，炎症疾患の治療薬として開発が進められている。この薬剤が濾胞性ヘルパーT細胞リンパ腫の治療薬として有用な可能性が示された。

Research Products

• [Journal Article] A single-cell atlas of non-haematopoietic cells in human lymph nodes and lymphoma reveals a landscape of stromal remodelling. (2021)
  • Author(s): Abe Y, Sakata-Yanagimoto M, Fujisawa M, Miyoshi H, Suehara Y, Hattori K, Kusakabe M, Sakamoto T, Nishikii H, Nguyen TB, Owada Y, Enomoto T, Sawa A, Bando H, Yoshida C, Tabata R, Terao T, Nakayama M, Ohshima K, Usuki K, Oda T, Matsue K, Chiba S
  • Journal Title: Nature cell biology Volume: 24 Issue: 4 Pages: 565-578
  • DOI: 10.1038/s41556-022-00866-3
  • Peer Reviewed / Open Access
• [Journal Article] Intratumor heterogeneity of lymphoma identified by multiregion sequencing of autopsy samples (2021)
  • Author(s): Makishima Kenichi、Suehara Yasuhito、Abe Yoshiaki、Hattori Keiichiro、Kusakabe Manabu、Matsuoka Ryota、Chiba Shigeru、Sakata‐Yanagimoto Mamiko
  • Journal Title: Cancer Science Volume: - Issue: 1 Pages: 362-364
  • DOI: 10.1111/cas.15178
  • Peer Reviewed / Open Access
• [Journal Article] Retrospective analyses of other iatrogenic immunodeficiency‐associated lymphoproliferative disorders in patients with rheumatic diseases (2021)
  • Author(s): Kaji D、Kusakabe M、Sakata‐Yanagimoto M、Makishima K、Suehara Y、Hattori K、Ota Y、Mitsuki T、Yuasa M、Kageyama K、Taya Y、Nishida A、Ishiwata K、Takagi S、Yamamoto H、Asano‐Mori Y、Ubara Y、Izutsu K、Uchida N、Wake A、Taniguchi S、Yamamoto G、Chiba S
  • Journal Title: British Journal of Haematology Volume: 195 Issue: 4 Pages: 585-594
  • DOI: 10.1111/bjh.17824
  • Peer Reviewed / Open Access
• [Journal Article] Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes (2020)
  • Author(s): Bernard E, Nannya Y, Hasserjian RP, Ogawa S, Papaemmanuil E
  • Journal Title: Nat Med Volume: 26(10) Issue: 10 Pages: 1549-1556
  • DOI: 10.1038/s41591-020-1008-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] VAV1 mutations contribute to development of T-cell neoplasms in mice (2020)
  • Author(s): Fukumoto Kota、Sakata-Yanagimoto Mamiko、Fujisawa Manabu、Sakamoto Tatsuhiro、Miyoshi Hiroaki、Suehara Yasuhito、Nguyen Tran B.、Suma Sakurako、Yanagimoto Shintaro、Shiraishi Yuichi、Chiba Kenichi、Bouska Alyssa、Kataoka Keisuke、Ogawa Seishi、Iqbal Javeed、Ohshima Koichi、Chiba Shigeru
  • Journal Title: Blood Volume: 136 Issue: 26 Pages: 3018-3032
  • DOI: 10.1182/blood.2020006513
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Advances in understanding of angioimmunoblastic T-cell lymphoma. (2020)
  • Author(s): Chiba S, Sakata-Yanagimoto M.
  • Journal Title: Leukemia Volume: 34 Issue: 10 Pages: 2592-2606
  • DOI: 10.1038/s41375-020-0990-y
  • Peer Reviewed / Open Access
• [Journal Article] RHOA mutation in follicular T‐cell lymphoma: Clinicopathological analysis of 16 cases (2020)
  • Author(s): Miyoshi Hiroaki、Sakata‐Yanagimoto Mamiko、Shimono Joji、Yoshida Noriaki、Hattori Keiichiro、Arakawa Fumiko、Yanagida Eriko、Takeuchi Mai、Yamada Kyohei、Suzuki Takaharu、Moritsubo Mayuko、Furuta Takuya、Chiba Shigeru、Ohshima Koichi
  • Journal Title: Pathology International Volume: 70 Issue: 9 Pages: 653-660
  • DOI: 10.1111/pin.12981
  • Peer Reviewed / Open Access
• [Journal Article] The prognostic impact of FLT3-ITD, NPM1 and CEBPa in cytogenetically intermediate-risk AML after first relapse (2020)
  • Author(s): Kurosawa Saiko、Yamaguchi Hiroki、Yamaguchi Takuhiro、Fukunaga Keiko、Yui Shunsuke、Kanamori Heiwa、Usuki Kensuke、Uoshima Nobuhiko、Yanada Masamitsu、Takeuchi Jin、Mizuno Ishikazu、Kanda Junya、Okamura Hiroshi、Yano Shingo、Tashiro Haruko、Shindo Takero、Chiba Shigeru、Tomiyama Junji、Inokuchi Koiti、Fukuda Takahiro
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 2 Pages: 200-209
  • DOI: 10.1007/s12185-020-02894-x
  • Peer Reviewed
• [Journal Article] Molecular pathogenesis of progression to myeloid leukemia from TET-insufficient status. (2020)
  • Author(s): Shrestha R, Sakata-Yanagimoto M, Maie K, Oshima M, Ishihara M, Suehara Y, Fukumoto K,1 Nakajima-Takagi Y, Matsui H, Kato T, Muto H, Sakamoto T, Kusakabe M, Nannya Y, Makishima H, Ueno H, Saiki R, Ogawa S, Chiba K, Shiraishi Y, Miyano S, Mouly E, Bernard OA, Inaba T, Koseki H, Iwama A, Chiba S
  • Journal Title: Blood Adv. Volume: 4(5) Issue: 5 Pages: 845-854
  • DOI: 10.1182/bloodadvances.2019001324
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dasatinib is an effective treatment for angioimmunoblastic T-cell lymphoma. (2020)
  • Author(s): Nguyen TB, Sakata-Yanagimoto M, Fujisawa M, Tanzima Nuhat S, Miyoshi H, Nannya Y, Hashimoto K, Fukumoto K, Bernard OA, Kiyoki Y, Ishitsuka K, Momose H, Sukegawa S, Shinagawa A, Suyama T, Sato Y, Nishikii H, Obara N, Kusakabe M, Yanagimoto S, Ogawa S, Ohshima K, Chiba S.
  • Journal Title: Cancer Res. 2020. Volume: - Issue: 9 Pages: 1875-1884
  • DOI: 10.1158/0008-5472.can-19-2787
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutations found in cell-free DNAs of patients with malignant lymphoma at remission can derive from clonal hematopoiesis (2019)
  • Author(s): Suehara Y, Sakata-Yanagimoto M, Hattori K, Kusakabe M, Nanmoku T, Sato T, Noguchi M, Chiba S
  • Journal Title: Cancer Sci Volume: 110(10) Issue: 10 Pages: 3375-3381
  • DOI: 10.1111/cas.14176
  • NAID: 120007133006
  • Peer Reviewed / Open Access
• [Presentation] A Single-Cell Atlas of Nonhematopoietic Cells in Human Lymph Node and Lymphoma Reveals Landscape of Stromal Remodeling (2021)
  • Author(s): Yoshiaki Abe, Mamiko Sakata-Yanagimoto, Manabu Fujisawa, et al., Tatsuya Oda, Kosei Matsue, Shigeru Chiba
  • Organizer: 63rd ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Germinal Center B Cells Derived from TET2-Mutated Clonal Hematopoiesis Provide a Microenviromental Niche for Tumor Cells in Angioimmunoblastic T-Cell Lymphoma (2021)
  • Author(s): Manabu Fujisawa, Tran B. Nguyen, Yoshiaki Abe, Yasuhito Suehara, Kota Fukumoto, Sakurako Suma, Kensuke Usuki, Kentaro Narita, Kosei Matsue, Naoya Nakamura, Shumpei Ishikawa, Fumihito Miura, Takashi Ito, Ayako Suzuki, Yutaka Suzuki, Satoru Takahashi, Shigeru Chiba, Mamiko Sakata-Yanagimoto
  • Organizer: 63rd ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] シングルセル解析による血管免疫芽球性 T 細胞リンパ腫の免疫プロファイルおよび腫瘍細胞不均一性の解明 (2021)
  • Author(s): Sakurako Suma, Manabu Fujisawa, Yoshiaki Abe, Yasuhito Suehara, Manabu Kusakabe, Takeshi Sugio, Koichi Akashi, Kosei Matsue, Naoya Nakamura, Ayako Suzuki, Yutaka Suzuki, Shigeru Chiba, Mamiko Sakata-Yanagimoto
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] 多領域シークエンスによる悪性リンパ腫の腫瘍不均一性の解析 (2021)
  • Author(s): 槇島健一，末原泰人，日下部学，千葉 滋，坂田（柳元）麻実子
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Tet2-deficient immune cells serve as niches to promote cancer progression: T-cell lymphoma and lung cancer models (2021)
  • Author(s): Mamiko Sakata-yanagimoto, Manabu Fujisawa, Nguyen Yen, Shigeru Chiba
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] JAK STAT pathway is a promising therapeutic target in acute erythroid leukemia (2020)
  • Author(s): June Takeda, Kenichi Yoshida，et al.，Shigeru Chiba，Hideyuki Nakazawa，Mingchung Kuo，Keisuke Kataoka，Ryunosuke Saiki，Masashi Sanada，Kensuke Usuki，Shuichi Miyawaki，Satoru Miyano，Jaroslaw Maciejewski，Hideki Makishima，Seishi Ogawa
  • Organizer: 第82回 日本血液学会学術集会
• [Presentation] The prognosis for OIIA-LPD was favorable regardless of response to immunosuppressant withdrawal (2020)
  • Author(s): Manabu Kusakabe, Daisuke Kaji，Mamiko Sakata-Yanagimoto，Yasuhito Suehara，Keiichiro Hattori，Yasunori Ota，Mitsuhiro Yuasa，Kosei Kageyama，Yuki Taya，Shinsuke Takagi，Hisashi Yamamoto，Yuki Mori，Naoyuki Uchida，Atsushi Wake，Shuichi Taniguchi，Go Yamamoto，Shigeru Chiba
  • Organizer: 第82回 日本血液学会学術集会
• [Presentation] Genetic landscape of subcutaneous panniculitis-like T-cell lymphoma (2020)
  • Author(s): Kenichi Makishima, Mamiko Sakata-Yanagimoto，Yasuhito Suehara，Yoshiaki Abe，Keiichiro Hattori，Yasuhisa Yokoyama，Hideki Makishima，Shigeru Chiba
  • Organizer: 第82回 日本血液学会学術集会
• [Presentation] VAV1 mutations contribute to development of T-cell neoplasms in mice (2020)
  • Author(s): Kota Fukumoto, Mamiko Sakata-Yanagimoto，Manabu Fujisawa，Tatsuhiro Sakamoto，Hiroaki Miyoshi，Yasuhito Suehara，Nguyen Tran，Sakurako Suma，Yuichi Shiraishi，Kenichi Chiba，Keisuke Kataoka，Seishi Ogawa，Koichi Ohshima，Shigeru Chiba
  • Organizer: 第82回 日本血液学会学術集会
• [Presentation] Distinctethnic, clinical, and genetic characteristics of der(1;7) in myelodysplastic syndromes. (2020)
  • Author(s): RurikaOkuda, Yasuhito annya, Yotaro Ochi, Kazuhisa Chonabayashi, Maria Creignou, Hideki Makishima, June Takeda, Ayana Kon, Satoru Miyano, Hiroshi Handa, Shigeru Chiba, Kazuma Ohyashiki, Torsten Haferlach, Eva Lindberg, Seishi Ogawa
  • Organizer: 第79回 日本癌学会学術総会
• [Presentation] Concurrent loss of Tet2 and Tet3 promotes leukemogenesis in mice (2019)
  • Author(s): Raksha Shrestha, Mamiko Sakata-Yanagimoto, Koichiro Maie, Motohiko Oshima, Yaeko Nakajima-Takagi, Hirotaka Matsui, Takayasu Kato, Hideharu Muto, Enguerran Mouly, Olivier A. Bernard, Haruhiko Koseki, Atsushi Iwama, Shigeru Chiba
  • Organizer: The 10th JSH INTERNATIONAL SYMPOSIUM 2019 in Ise-Shima
  • Int'l Joint Research
• [Presentation] Targeted sequencing and IgH rearrangement status revealed branching evolution pattern of SMZL and DLBCL (2019)
  • Author(s): Manabu Kusakabe, Mamiko Sakata-Yanagimoto, Yasuhito Suehara, Keiichiro Hattori, Toru Nanmoku, Tatsuhiro Sakamoto, Yasuhisa Yokoyama, Takayasu Kato, Naoki Kurita, Hidekazu Nishikii, Naoshi Obara, Masafumi Muratani, Yuichi Hasegawa, Shigeru Chiba
  • Organizer: The 10th JSH INTERNATIONAL SYMPOSIUM 2019 in Ise-Shima
  • Int'l Joint Research
• [Presentation] Allelic inactivation of Tets is responsible for leukemic transformation in mice already losing Tet functions in multiple alleles (2019)
  • Author(s): Mamiko Sakata-Yanagimoto, Shrestha Raksha, Koichiro Maie, Motohiko Oshima, Yaeko Nakajima-Takagi, Hirotaka Matsui, Takayasu Kato, Hideharu Muto, Enguerran Mouly, Olivier A. Bernard, Haruhiko Koseki, Atsushi Iwama, Shigeru Chiba
  • Organizer: The 17th Stem Cell Research Symposium
  • Int'l Joint Research
• [Presentation] Targeting T-cell receptor signaling pathway by dasatinib in relapsed/refractory angioimmunoblastic T-cell lymphoma (2019)
  • Author(s): Yusuke Kiyoki, Mamiko Sakata-Yanagimoto, Tran B. Nguyen, Manabu Fujisawa, Yasuhito Nanya, Shigeru Chiba, et al.
  • Organizer: The 24th Congress of EHA
  • Int'l Joint Research
• [Presentation] Targeting T-cell receptor signaling pathway by dasatinib in relapsed/refractory angioimmunoblastic T-cell lymphoma (2019)
  • Author(s): 清木祐介，坂田（柳元）麻実子，Tran B. Ngyen，藤澤 学，南谷泰仁，石塚幹太郎，百瀬春佳，助川慎一郎，品川 篤，周山拓也，佐藤祐二，錦井秀和，小原 直，日下部学，加藤貴康，横山泰久，栗田尚樹，長谷川雄一，小川誠司，千葉 滋
  • Organizer: 第59回 日本リンパ網内系学会総会
• [Presentation] Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specifiedrevealed by comprehensive genetic profiling (2019)
  • Author(s): 綿谷陽作，佐藤康晴，三好寛明，坂本佳奈，西田賢司，祇園由佳，坂田（柳元）麻実子，中村信彦，平本展大，白石友一，宮野 悟，真田 昌，千葉 滋，石川隆之，鶴見 寿，竹内賢吾，大島孝一，吉野 正，小川誠司，片岡圭亮
  • Organizer: 第59回 日本リンパ網内系学会総会
• [Presentation] Targeted therapy for tumor cells and microenvironmental cellsderived from clonal hematopoiesis (2019)
  • Author(s): Mamiko Sakata-Yanagimoto, Manabu Fujisawa, Shigeru Chiba
  • Organizer: 第78回 日本癌学会学術総会
  • Invited
• [Presentation] 血管免疫芽球性T細胞リンパ腫および類縁疾患のゲノム解析 (2019)
  • Author(s): 末原泰人，坂田(柳元)麻実子，服部圭一朗，日下部学，福本浩太，藤澤 学，千葉健一，白石友一，宮野 悟，小川誠司，末永孝生，千葉 滋
  • Organizer: 第78回 日本癌学会学術総会
• [Presentation] Targeting T-Cell Receptor Signaling as Angioimmunoblastic T-CellLymphoma Treatment (2019)
  • Author(s): Tran B. Nguyen, Mamiko Sakata-Yanagimoto, Manabu Fujisawa, Hiroaki Miyoshi, Yasuhito Nannya, Takuya Suyama, Yuji Sato, Hidekazu Nishikii, Naoshi Obara, Manabu Kusakabe, Seishi Ogawa, Kouichi Ohshima, Shigeru Chiba
  • Organizer: 第78回 日本癌学会学術総会
  • Invited
• [Presentation] 再発難治性血管免疫芽球性T細胞リンパ腫を対象としたT細胞受容体シグナルに対する標的治療 (2019)
  • Author(s): 坂田（柳元）麻実子，清木祐介, トラン グエン, 藤澤 学, 南谷泰仁, 石塚幹太郎, 百瀬春佳, 品川篤司, 周山拓也, 佐藤祐二, 錦井秀和, 小原 直, 日下部学, 加藤貴康, 横山泰久, 栗田尚樹, 長谷川雄一, 小川誠司, 千葉 滋
  • Organizer: 第81回 日本血液学会学術集会
• [Presentation] 血管免疫芽球性T細胞リンパ腫および類縁疾患のゲノム解析 (2019)
  • Author(s): 末原泰人，坂田（柳元）麻実子, 服部圭一朗, 日下部学, 福本浩太, 藤澤 学, 千葉健一, 白石友一, 宮野 悟, 小川誠司, 末永孝生, 千葉 滋
  • Organizer: 第81回 日本血液学会学術集会
• [Presentation] VAV1 Mutations Contributes to the Development of T-Cell Malignancies in Mice (2019)
  • Author(s): Kota Fukumoto, Mamiko Sakata-Yanagimoto, Manabu Fujisawa, Tatsuhiro Sakamoto, Tran B. Nguyen, Sakurako Suma, Hiroaki Miyoshi, Koichi Ohshima, Keisuke Kataoka, Seishi Ogawa, Shigeru Chiba
  • Organizer: 61st ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Clinicopathological Analysis of “Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders” Reveals a Favorable Outcome Independent of the Effectiveness of Methotrexate Discontinuation in Autoimmune Disease Patients (2019)
  • Author(s): Daisuke Kaji, Manabu Kusakabe, Mamiko Sakata-Yanagimoto, Yasuhito Suehara, Keiichiro Hattori, Yasunori Ota, Mitsuhiro Yuasa, Kosei Kageyama, Yuki Taya, Shinsuke Takagi, Hisashi Yamamoto, Yuki Asano-Mori, Naoyuki Uchida, Atsushi Wake, Shuichi Taniguchi, Go Yamamoto, Shigeru Chiba
  • Organizer: 61st ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Remarks] 筑波大学血液内科
  • URL: http://www.ketsunai.com/
• [Remarks] 筑波大学血液内科
  • URL: http://www.ketsunai.com