A comprehensive search for miRNAs regulated by histone deacetylase in malignant lymphoma

• Project/Area Number: 17K16178
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Akita University (2019); Kameda College of Health Sciences (2017-2018)
• Principal Investigator: Kitadate Akihiro 秋田大学, 医学部附属病院, 医員 (90791559)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 悪性リンパ腫 / T細胞リンパ腫 / HDAC / HDAC阻害剤 / CCR4 / ボリノスタット / microRNA / Ｔ細胞リンパ腫 / ケモカインレセプター

Outline of Final Research Achievements

We found that HDAC inhibitors restore expression of many tumor suppressive microRNAs. In particular, it was revealed that restoration of miR-150 expression caused a decrease in the expression of chemokine receptor CCR6. Moreover, we found that the expression of another chemokine receptor, CCR4, is also decreased. Importantly, in vitro studies revealed that the efficacy of the anti-CCR4 antibody mogamulizumab may be diminished by pre-treatment of HDAC inhibitors. These findings may have important implications for the establishment therapeutic strategies for T-cell lymphoma.

Academic Significance and Societal Importance of the Research Achievements

HDAC阻害剤はT細胞リンパ腫における新規治療薬として登場したが、その作用機序は十分明らかではなかった。今回HDAC阻害剤ががん抑制的microRNAの発現を回復させ、ケモカインレセプターの発現を低下させることを見出した。特に重要な点として、ケモカインレセプターCCR4の発現を低下させることが挙げられる。CCR4はT細胞リンパ腫における別の新規治療薬であるモガムリズマブの標的抗原である。これにより、HDAC阻害剤とモガムリズマブの併用が有用でないことが示唆され、T細胞リンパ腫の最適な治療戦略確立に重要な示唆をもたらすものと思われる。

Research Products

• [Journal Article] Incisional random skin biopsy, not punch biopsy, is an appropriate method for diagnosis of intravascular large B‐cell lymphoma: a clinicopathological study of 25 patients (2019)
  • Author(s): Enzan N.、Kitadate A.、Tanaka A.、Matsue K.
  • Journal Title: British Journal of Dermatology Volume: 181 Issue: 1 Pages: 200-201
  • DOI: 10.1111/bjd.17603
  • Peer Reviewed
• [Journal Article] Pre-treatment CD38-positive regulatory T cells affect the durable response to daratumumab in relapsed/refractory multiple myeloma patients (2019)
  • Author(s): Kitadate Akihiro、Kobayashi Hiroki、Abe Yoshiaki、Narita Kentaro、Miura Daisuke、Takeuchi Masami、Matsue Kosei
  • Journal Title: Haematologica Volume: 105 Issue: 1 Pages: e37-e40
  • DOI: 10.3324/haematol.2019.219683
  • Peer Reviewed / Open Access
• [Journal Article] Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive mature T-cell lymphomas. (2018)
  • Author(s): Kitadate A, Ikeda S, Abe F, Takahashi N, Shimizu N, Matsue K, Tagawa H.
  • Journal Title: Haematologica Volume: 103(1) Issue: 1 Pages: 126-135
  • DOI: 10.3324/haematol.2017.177279
  • Peer Reviewed / Open Access
• [Presentation] Baseline total lesion glycolysis combined with interim PET/CT is a robust predictor of outcome in patients with peripheral T-cell lymphoma (2019)
  • Author(s): Akihiro Kitadate, Kentaro Narita, Kota Fukumoto, Toshiki Terao, Takafumi Tsushima, Hiroki Kobayashi, Yoshiaki Abe, Daisuke Miura, Masami Takeuchi, Youichi Machida, Naoto Takahashi, Kosei Matsue
  • Organizer: 61th ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Prognostic value of interim and end-of-treatment PET-CT in patients with mature T-cell and NK-cell lymphomas: A 10-Year Single Institution Study (2018)
  • Author(s): Akihiro Kitadate
  • Organizer: 60th ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive malignant lymphomas (2017)
  • Author(s): Akihiro Kitadate, Sho Ikeda, Fumito Abe, Naoto Takahashi, Norio Shimizu, Kosei Matsue and Hiroyuki Tagawa
  • Organizer: 59th ASH Annual Meeting and Exposition
  • Invited