Development of methods for elimination of multiple myeloma stem cells targeting constitutively activated integrin beta 7

• Project/Area Number: 17H04207
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: Hosen Naoki 大阪大学, 医学系研究科, 教授 (10456923)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 多発性骨髄腫 / インテグリン / 癌

Outline of Final Research Achievements

We searched for molecules that cause constitutive activation of integrin β7 in myeloma cells by screening with CRISPR gRNA library or cDNA derived from myeloma cells, but no candidate molecule was obtained. However, we found that the antigen epitope for the activated integrin β7 was expressed upon induction of endoplasmic reticulum stress, a major feature of myeloma cells, with tunicamycin or thapsigargin. Based on these results, we hypothesized that β7 integrin may have a unique conformation in myeloma that is different from the physiological activated conformation, and started a collaboration with a structural biologist.

Academic Significance and Societal Importance of the Research Achievements

β7インテグリンでは生理的な活性化コンフォーメーションと似て非なる「骨髄腫に特有のコンフォーメーション」が存在する可能性を示唆し、真の意味でがんと正常との間に蛋白質の“形”の違いがあるかもしれないという新しいコンセプトを提示することができた。今後このコンセプトを検証し、正しいことが実証できれば、他の様々ながんにおいて様々な蛋白質のがん特異的なコンフォメーションの存在が同定できる可能性が広がり、新たながん治療の開発に役立つ可能性がある。

Research Products

• [Journal Article] Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma (2019)
  • Author(s): Hosen Naoki
  • Journal Title: Cancers Volume: 11 Issue: 12 Pages: 2024-2024
  • DOI: 10.3390/cancers11122024
  • NAID: 130007496853
  • Peer Reviewed
• [Presentation] The Activated Conformation of Integrin β7 is a Novel Multiple Myeloma-Specific Target for CAR T-cell Therapy. (2020)
  • Author(s): Naoki Hosen
  • Organizer: 2nd European CAR T cell meeting
  • Int'l Joint Research / Invited
• [Presentation] The Activated Conformation of Integrin β7 is a Novel Multiple Myeloma-Specific Target for CAR T-cell Therapy. (2019)
  • Author(s): Naoki Hosen
  • Organizer: The 24th Congress European Hematology Assocoation
  • Int'l Joint Research / Invited