Investigation of molecular mechanisms for constitutive IRF4 expression in T-cell malignancies

• Project/Area Number: 21H02775
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Hokkaido University
• Principal Investigator: Nakagawa Masao 北海道大学, 医学研究院, 助教 (80435859)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2023: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2022: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2021: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 成人T細胞性白血病リンパ腫 / T細胞性リンパ腫 / IRF4 / PD-L1 / CAR-T / ATLL / CRIPSR / T細胞性腫瘍 / CRISPR

Outline of Research at the Start

成人T細胞性白血病リンパ腫は我が国に高頻度にみられるT細胞性腫瘍であり、既存治療に対して高度に抵抗性である。申請者は2018年転写因子IRF4が成人T細胞性白血病リンパ腫細胞増殖・生存に必須であることを見出した。IRF4発現は、正常T細胞ではT細胞受容体-NF-kBあるいはNFATにより誘導されるが、申請者の最近の研究結果から成人T細胞性白血病リンパ腫では全く別の機序が存在することがわかってきた。本研究ではCRISPR等を活用した包括的な機能解析を行いIRF4の恒常的発現維持のメカニズムを明らかし、T細胞性腫瘍に対する新規治療の基盤開発を目指す。

Outline of Final Research Achievements

Compound library screening revealed a compound, which can reduce IRF4 protein expression in multiple T-cell lymphoma cell lines, including adult T-cell leukemia lymphoma cell lines. ATACseq analysis was performed to analyze the mechanism of conctitutive IRF4 expression, but no common open chromatin region around the IRF4 locus was found among multiple cases. Tissue microarray analysis of T-cell lymphomas revealed the expression frequency of IRF4 and BATF3 by disease type. PD-L1-CAR-T generated in this project exhibited superior cytotoxic activity against PD-L1 high expressing T-cell lymphoma cells.

Academic Significance and Societal Importance of the Research Achievements

成人T細胞性白血病リンパ腫を含む一部のT細胞性リンパ腫細胞に必須の遺伝子であるIRF4の発現制御のメカニズムの一端および発現頻度のを明らかにしたことで、今後の治療法開発へ基盤的治知見となる。抗PD-1抗体で病勢増悪の可能性のある成人T細胞性白血病リンパ腫に対して、PD-L1-CAR-T開発への可能性を示した。

Research Products

• [Int'l Joint Research] Fox Chase Cancer Center(米国)
• [Int'l Joint Research] National Cancer Institute, NIH/Fox Chase Cancer Center(米国)
• [Int'l Joint Research] National Cancer Institute, NIH/Fox Chase Cancer Center(米国)
• [Journal Article] Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma (2024)
  • Author(s): Chiba Masahiro、Shimono Joji、Suto Keito、Ishio Takashi、Endo Tomoyuki、Goto Hideki、Hasegawa Hiroo、Maeda Michiyuki、Teshima Takanori、Yang Yibin、Nakagawa Masao
  • Journal Title: Blood Volume: 143 Issue: 14 Pages: 1379-1390
  • DOI: 10.1182/blood.2023021423
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis and therapeutic targeting of the EP300 and CREBBP acetyltransferases in anaplastic large cell lymphoma and Hodgkin lymphoma (2022)
  • Author(s): Wei Wei、Song Zhihui、Chiba Masahiro、Wu Wenjun、Jeong Subin、Zhang Jing-Ping、Kadin Marshall E.、Nakagawa Masao、Yang Yibin
  • Journal Title: Leukemia Volume: 37 Issue: 2 Pages: 396-407
  • DOI: 10.1038/s41375-022-01774-z
• [Journal Article] Genome-wide CRISPR screens identify CD48 defining susceptibility to NK cytotoxicity in peripheral T-cell lymphomas (2022)
  • Author(s): Chiba Masahiro、Shimono Joji、Ishio Takashi、Takei Norio、Kasahara Kohei、Ogasawara Reiki、Ara Takahide、Goto Hideki、Izumiyama Koh、Otsuguro Satoko、Perera Liyanage P.、Hasegawa Hiroo、Maeda Michiyuki、Hashino Satoshi、Maenaka Katsumi、Teshima Takanori、Waldmann Thomas A.、Yang Yibin、Nakagawa Masao
  • Journal Title: Blood Volume: 140 Issue: 18 Pages: 1951-1963
  • DOI: 10.1182/blood.2022015646
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gilteritinib enhances graft-versus-leukemia effects against FLT3-ITD mutant leukemia after allogeneic hematopoietic stem cell transplantation (2022)
  • Author(s): Zhang Zixuan、Hasegawa Yuta、Hashimoto Daigo、Senjo Hajime、Kikuchi Ryo、Chen Xuanzhong、Yoneda Kazuki、Sekiguchi Tomoko、Kawase Tatsuya、Tsuzuki Hirofumi、Ishio Takashi、Ara Takahide、Ohigashi Hiroyuki、Nakagawa Masao、Teshima Takanori
  • Journal Title: Bone Marrow Transplantation Volume: - Issue: 5 Pages: 775-780
  • DOI: 10.1038/s41409-022-01619-4
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma (2022)
  • Author(s): Ishio Takashi、Kumar Sarvesh、Shimono Joji、Daenthanasanmak Anusara、Dubois Sigrid、Lin Yuquan、Bryant Bonita、Petrus Michael N.、Bachy Emmanuel、Huang Da Wei、Yang Yandan、Green Patrick L.、Hasegawa Hiroo、Maeda Michiyuki、Goto Hideki、Endo Tomoyuki、Yokota Takashi、Hatanaka Kanako C.、Hatanaka Yutaka、Tanaka Shinyaら
  • Journal Title: Blood Volume: 139 Issue: 10 Pages: 1541-1556
  • DOI: 10.1182/blood.2021012734
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] CRISPR Screen Identifies CD48 As A Key Molecule For NK Cell Immunity In Peripheral T-cell Lymphomas (2023)
  • Author(s): Masahiro Chiba, Joji Shimono, Takashi Ishio, Norio Takei, Kohei Kasahara, Reiki Ogasawara, Takahide Ara, Hideki Goto, Koh Izumiyama, Satoko Otsuguro, Liyanage P. Perera, Hiroo Hasegawa, Michiyuki Maeda, Satoshi Hashino, Katsumi Maenaka, Takanori Teshima, Thomas A. Waldmann, Yibin Yang and Masao Nakagawa
  • Organizer: The 13th JSH International Symposium 2023 in Tsukuba
  • Int'l Joint Research
• [Presentation] CRISPR screen identifies APC/C and SLC39A7 as intrinsic regulators for BV sensitivity in PTCL cells (2023)
  • Author(s): Keito Suto, Masahiro Chiba, Takashi Ishio, Takanori Teshima, Masao Nakagawa
  • Organizer: 第85回日本血液学会総会
• [Presentation] CRISPR screen identifies ZNF451 regulating sensitivity to topoisomerase 2 inhibitors in PTCL (2023)
  • Author(s): Keito Suto, Masahiro Chiba, Takashi Ishio, Takanori Teshima, Masao Nakagawa
  • Organizer: 第85回日本血液学会総会
• [Presentation] Genome-wide CRISPR Screen Identifies MAD2L1BP, ANAPC15 and SLC39A7 as Intrinsic Regulators for Brentuximab Vedotin Sensitivity in Peripheral T-cell Lymphoma Cells (2023)
  • Author(s): Keito Suto, Masahiro Chiba, Takashi Ishio, Hideki Goto, Tomoyuki Endo, Michiyuki Maeda, Takanori Teshima, Masao Nakagawa
  • Organizer: The 65th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Genome-wide CRISPR Screen Identifies ZNF451 Regulating Sensitivity to Topoisomerase 2 Inhibitors in Peripheral T-cell Lymphoma Cells (2023)
  • Author(s): Keito Suto, Masahiro Chiba, Takashi Ishio, Hideki Goto, Tomoyuki Endo, Michiyuki Maeda, Takanori Teshima, Masao Nakagawa
  • Organizer: The 65th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Whole-genome CRISPR library screens identify CD48 as an essential molecule in adult T-cell leukemia/lymphoma for defining susceptibility to natural killer cell-mediated cytotoxicity (2021)
  • Author(s): Masahiro Chiba, Joji Shimono, Takashi Ishio, Hideki Goto, Satoshi Hashino, Takanori Teshima, Masao Nakagawa
  • Organizer: The European Hematology Association （EHA） 2021 Virtual Congress
  • Int'l Joint Research
• [Presentation] CRISPR screen identifies CD48 as a key molecule for evasion from NK cell surveillance in PTCL (2021)
  • Author(s): 千葉雅尋, 下埜城嗣, 石尾 崇, 須藤啓斗, 後藤秀樹, 橋野 聡, 豊嶋崇徳, 中川雅夫
  • Organizer: 第83回日本血液学会学術集会
• [Book] 血液内科 第87巻第3号 ATLLおよびPTCLsにおけるCD48発現低下とNK細胞の攻撃回避 (2023)
  • Author(s): 千葉 雅尋、中川 雅夫
  • Total Pages: 356
  • Publisher: 科学評論社
• [Book] 月刊血液内科 (Hematology) (2022)
  • Author(s): 石尾崇、中川雅夫
  • Total Pages: 5
  • Publisher: 科学評論社
• [Book] 血液内科 第84巻第3号 未分化大細胞リンパ腫の病態と治療の考え方 (2021)
  • Author(s): 中川 雅夫
  • Total Pages: 6
  • Publisher: 科学評論社
• [Remarks] 北海道大学大学院医学研究院 血液内科学教室 リンパ系腫瘍グループ
  • URL: https://www.hokudai-hematology.jp/research/basic/03/
• [Remarks] 北海道大学大学院医学研究院 血液内科学教室 リンパ系腫瘍グループ
  • URL: https://www.hokudai-hematology.jp/medical/basic-research/index3.html
• [Remarks] 北海道大学大学院医学研究院 血液内科学教室 リンパ系腫瘍グループ
  • URL: http://www.hokudai-hematology.jp/medical/basic-research/index3.html