Microvesicle-mediated interaction between multiple myeloma cells and bone marrow stroma

• Project/Area Number: 25461434
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical University
• Principal Investigator: Furukawa Yusuke 自治医科大学, 医学部, 教授 (00199431)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 多発性骨髄腫 / 接着耐性 / 間質細胞 / Microvesicle / microRNA

Outline of Final Research Achievements

Multiple myeloma cells acquire the resistance to anti-cancer drugs via interaction with bone marrow stroma (cell adhesion-mediated drug resistance). In this study, we investigated the role of circulating microvescles (cMV) produced by myeloma cells in cell adhesion-mediated drug resistance. We isolated cMV from the co-culcture supernatant of myeloma cells and human bone marrow-derived stromal cells.We then extracted total RNA form cMV and subjected them to microRNA arrays, and found that myeloma-derived cMV was very rich in miR-155 and mir-135b. Functional studies revealed that the expression level of miR-155 was positively correlated with the sensitivity of myeloma cells to proteasome inhibitors. We are currently investigating the precise mechanisms by which miR-155 determines the sensitivity of myeloma cells to proteasome inhibitors.

Research Products

• [Journal Article] Phosphorylation-mediated EZH2 Inactivation Promotes Drug Resistance in Multiple Myeloma. (2015)
  • Author(s): Kikuchi, J., Koyama, D., Wada, T., Izumi, T., Hofgaard, P.O., Bogen, B. and Furukawa, Y.
  • Journal Title: The Journal of Clinical Investigation Volume: 125 Pages: 4375-4390
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Overexpression of the Shortest Isoform of Histone Demethylase LSD1 Primes Hematopoietic Stem Cells for Malignant Transformation. (2015)
  • Author(s): Wada, T., Koyama, D., Kikuchi, J., Honda, H. and Furukawa, Y.
  • Journal Title: Blood Volume: 125 Pages: 3731-3746
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Molecular Pathogenesis of Multiple Myeloma. (2015)
  • Author(s): Furukawa, Y. and Kikuchi, J.
  • Journal Title: International Journal of Clinical Oncology Volume: 20 Pages: 413-422
  • NAID: 40022340491
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Overexpression of the Shortest Isoform of Histone Demethylase LSD1 Primes Hematopoietic Stem Cells for Malignant Transformation. (2015)
  • Author(s): Wada, T., Koyama, D., Kikuchi, J., Honda, H. and Furukawa, Y.
  • Journal Title: BLOOD Volume: 125 Pages: 0000-0000
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia. (2014)
  • Author(s): Koyama D, Kikuchi J, Hiraoka N, Wada T, Kurosawa H, Chiba S, and Furukawa Y.
  • Journal Title: Leukemia Volume: in press Issue: 6 Pages: 1216-1226
  • DOI: 10.1038/leu.2013.366
  • Peer Reviewed / Open Access
• [Journal Article] Arf tumor suppressor disrupts the oncogenic positive feedback loop including c-Myc and DDX5. (2014)
  • Author(s): Tago K, Funakoshi-Tago M, Itoh H, Furukawa Y, Kikuchi J, Kato T, Suzuki K, Yanagisawa K
  • Journal Title: Oncogene Volume: 未定 Issue: 3 Pages: 310-318
  • DOI: 10.1038/onc.2013.561
  • Peer Reviewed / Open Access
• [Journal Article] Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies. (2014)
  • Author(s): Hiraoka N, Kikuchi J, Yamauchi T, Koyama D, Wada T, Uesawa M, Akutsu M, Mori S, Nakamura Y, Ueda T, Kano Y, Furukawa Y.
  • Journal Title: Plos One Volume: 13 Issue: 3 Pages: e90675-e90675
  • DOI: 10.1371/journal.pone.0090675
  • Peer Reviewed / Open Access
• [Journal Article] Suitable drug combination with bortezomib for multiple myeloma under stroma-free conditions and in contact with fibronectin or bone marrow stromal cells. (2014)
  • Author(s): Kikuchi J, Koyama D, Mukai YH, and Furukawa Y.
  • Journal Title: Int J Hematol Volume: in press Issue: 6 Pages: 726-736
  • DOI: 10.1007/s12185-014-1573-3
  • Peer Reviewed
• [Remarks]
  • URL: http://www.jichi.ac.jp/stem/index.html