mir-17~92 cluster in mantle cell lymphoma

• Project/Area Number: 19K17867
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Tsukamoto Taku 京都府立医科大学, 医学(系)研究科(研究院), 助教 (50825049)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: マントル細胞リンパ腫 / B細胞受容体シグナル / mir-17~92 cluster / Pulldown-seq / ナイーブB細胞

Outline of Research at the Start

マントル細胞リンパ腫(MCL)の発生母地であるナイーブB細胞では、通常、B細胞受容体(BCR)シグナル経路の活性は低いのに対し、MCLではBCRシグナル活性の過剰活性化が認められる。これまでMCLにおけるBCR活性化機序は未解明であったが、micro RNAであるmir-17~92 clusterの高発現がその原因となる可能性がある。本研究ではmir-17~92 clusterの網羅的標的探索を通じてMCL特異的なBCRシグナル活性化の分子メカニズムを解明し、その知見に基づいた新規BCRシグナル標的療法の開発に挑戦する。

Outline of Final Research Achievements

To uncover the targets of mir-17~92, an oncogenic micro RNA cluster, in mantle cell lymphoma, we performed unbiased sequencing analysis using pull-down method with micro RNA mimics. We identified some mir-17~92 cluster target genes involved in B cell receptor signaling, i.e., BTG2 and FCGR2A/B.

Academic Significance and Societal Importance of the Research Achievements

マントル細胞リンパ腫におけるB細胞受容体シグナル活性化機序の解明は、同経路の標的治療抵抗性獲得という臨床上のアンメットニードの克服において重要な課題であるが、本研究においてその知見の一端を明らかにできたことは、今後のマントル細胞リンパ腫における治療成績向上に寄与する可能性を有している。かねてから、様々ながんの発生・病態形成に重要な役割をはたすとされるがん関連micro RNA mir-17~92 clusterの標的分子の網羅的解析結果は、MCLのみならず多くの悪性腫瘍の病態解明につながることが期待される。

Research Products

• [Journal Article] EWSR1 overexpression is a pro-oncogenic event in multiple myeloma (2021)
  • Author(s): Nishiyama D, Chinen Y, Isa R, Fujibayashi Y, Kuwahara-Ota S, Yamaguchi J, Takimoto-Shimomura T, Matsumura-Kimoto Y, Tsukamoto T, Shimura Y, Kobayashi T, Horiike S, Taniwaki M, Handa H, Kuroda J.
  • Journal Title: Int J Hematol Volume: 113 Issue: 3 Pages: 381-394
  • DOI: 10.1007/s12185-020-03027-0
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-specific transcript variants of cyclin D1 in mantle cell lymphoma and multiple myeloma with chromosome 11q13 abnormalities (2020)
  • Author(s): Chinen Yoshiaki、Tsukamoto Taku、Maegawa-Matsui Saori、Matsumura-Kimoto Yayoi、Takimoto-Shimomura Tomoko、Tanba Kazuna、Mizuno Yoshimi、Fujibayashi Yuto、Kuwahara-Ota Saeko、Shimura Yuji、Kobayashi Tsutomu、Horiike Shigeo、Taniwaki Masafumi、Kuroda Junya
  • Journal Title: Experimental Hematology Volume: - Pages: 45-53.e1
  • DOI: 10.1016/j.exphem.2020.02.004
  • Peer Reviewed / Open Access
• [Journal Article] Lenalidomide and pomalidomide potently interfere with induction of myeloid-derived suppressor cells in multiple myeloma (2020)
  • Author(s): Kuwahara-Ota S, Shimura Y, Steinebach C, Isa R, Yamaguchi J, Nishiyama D, Fujibayashi Y, Takimoto-Shimomura T, Mizuno Y, Matsumura-Kimoto Y, Tsukamoto T, Chinen Y, Kobayashi T, Horiike S, Taniwaki M, Gutschow M, Kuroda J
  • Journal Title: Br J Haematol Volume: 191 Issue: 5 Pages: 784-795
  • DOI: 10.1111/bjh.16881
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serine-227 in the N-terminal kinase domain of RSK2 is a potential therapeutic target for mantle cell lymphoma (2020)
  • Author(s): Matsumura-Kimoto Y, Tsukamoto T, Shimura Y, Chinen Y, Tanba K, Kuwahara-Ota S, Fujibayashi Y, Nishiyama D, Isa R, Yamaguchi J, Kawaji-Kanayama Y, Kobayashi T, Horiike S, Taniwaki M, Kuroda J
  • Journal Title: Cancer Med Volume: 9 Issue: 14 Pages: 5185-5199
  • DOI: 10.1002/cam4.3136
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma (2020)
  • Author(s): Fujibayashi Y, Isa R, Nishiyama D, Sakamoto-Inada N, Kawasumi N, Yamaguchi J, Kuwahara-Ota S, Matsumura-Kimoto Y, Tsukamoto T, Chinen Y, Shimura Y, Kobayashi T, Horiike S, Taniwaki M, Handa H, Kuroda J
  • Journal Title: Cancers Volume: 12 Issue: 8 Pages: 2206-2206
  • DOI: 10.3390/cancers12082206
  • Peer Reviewed / Open Access
• [Journal Article] BRD4-Regulated Molecular Targets in Mantle Cell Lymphoma: Insights into Targeted Therapeutic Approach. (2020)
  • Author(s): Tsukamoto T, Nakahata S, Sato R, Kanai A, Nakano M, Chinen Y, Maegawa-Matsui S, Matsumura-Kimoto Y, Takimoto-Shimomura T, Mizuno Y, Kuwahara-Ota S, Kawaji Y, Taniwaki M, Inaba T, Tashiro K, Morishita K, Kuroda J
  • Journal Title: Cancer Genomics Proteomics Volume: 17 Pages: 77-89
  • Peer Reviewed / Open Access