Bone marrow stromal cells protect myeloma cells from bortezomib induced apoptosis by suppressing microRNA-15a expression

Leuk Lymphoma. 2011 Sep;52(9):1787-94. doi: 10.3109/10428194.2011.576791. Epub 2011 May 3.


Despite unsurpassed anti-tumor activity of bortezomib for multiple myeloma (MM), drug resistance has emerged as a challenge, especially when MM cells adhere to the stroma. This study aimed to determine whether bone marrow stromal cells (BMSCs) have a role in the development of chemoresistance in MM. Our data demonstrate that the secretion of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and cell-to-cell contact with microenvironment-derived stromal cells from patients with multiple myeloma (MM-BMSCs) significantly decreased the sensitivity of myeloma cells to bortezomib treatment. Mechanistically, we found that microRNA (miRNA)- 15a expression was up-regulated in U266 and NCI-H929 cells treated by bortezomib, which was inhibited by MM-BMSCs. miRNA-15a transfected myeloma cells were arrested in G1/S checkpoint and secreted less VEGF compared to control transfected cells, although no significant difference was found in VEGF mRNA levels. In conclusion, our data suggest that via suppressing miRNA-15a expression, BMSCs provide survival support and protect myeloma cells from bortezomib induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Bone Marrow Cells / metabolism*
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Leukemic
  • Humans
  • MicroRNAs / genetics*
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / metabolism*
  • Pyrazines / pharmacology*
  • Stromal Cells / metabolism
  • Tumor Microenvironment
  • Vascular Endothelial Growth Factor A / metabolism


  • Boronic Acids
  • MIRN15 microRNA, human
  • MicroRNAs
  • Pyrazines
  • Vascular Endothelial Growth Factor A
  • Bortezomib