CCR10/CCL27 crosstalk contributes to failure of proteasome-inhibitors in multiple myeloma

Oncotarget. 2016 Nov 29;7(48):78605-78618. doi: 10.18632/oncotarget.12522.


The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines.In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor.From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients.

Keywords: CCL27; CCR10; drug resistance; myeloma; stroma cells.

MeSH terms

  • Aged
  • Apoptosis / drug effects
  • Bortezomib / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chemokine CCL27 / metabolism*
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Male
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / enzymology
  • Multiple Myeloma / genetics
  • Multiple Myeloma / pathology
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology*
  • RNA Interference
  • Receptor Cross-Talk / drug effects*
  • Receptors, CCR10 / genetics
  • Receptors, CCR10 / metabolism*
  • Receptors, Interleukin-10 / genetics
  • Receptors, Interleukin-10 / metabolism
  • Signal Transduction / drug effects*
  • Transfection
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays


  • CCL27 protein, human
  • CCR10 protein, human
  • Chemokine CCL27
  • IL10 protein, human
  • Proteasome Inhibitors
  • Receptors, CCR10
  • Receptors, Interleukin-10
  • Interleukin-10
  • Bortezomib
  • Proteasome Endopeptidase Complex