Title | Molecular events underlying interleukin-6 independence in a subclone of the CMA-03 multiple myeloma cell line. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Verdelli D, Nobili L, Todoerti K, Mosca L, Fabris S, D'Anca M, Pellegrino E, Piva R, Inghirami G, Capelli C, Introna M, Baldini L, Chiaramonte R, Lombardi L, Neri A |
Journal | Genes Chromosomes Cancer |
Volume | 53 |
Issue | 2 |
Pagination | 154-67 |
Date Published | 2014 Feb |
ISSN | 1098-2264 |
Keywords | Apoptosis, Boronic Acids, Bortezomib, Cell Line, Tumor, Humans, Interleukin-6, MAP Kinase Signaling System, Multiple Myeloma, NF-kappa B, Pyrazines, Signal Transduction, Transcriptome |
Abstract | We explored the molecular mechanisms involved in the establishement of CMA-03/06, an IL-6-independent variant of the multiple myeloma cell line CMA-03 previously generated in our Institution. CMA-03/06 cells grow in the absence of IL-6 with a doubling time comparable with that of CMA-03 cells; neither the addition of IL6 (IL-6) to the culture medium nor co-culture with multipotent mesenchymal stromal cells increases the proliferation rate, although they maintain the responsiveness to IL-6 stimulation as demonstrated by STAT1, STAT3, and STAT5 induction. IL-6 independence of CMA-03/06 cells is not apparently due to the development of an autocrine IL-6 loop, nor to the observed moderate constitutive activation of STAT5 and STAT3, since STAT3 silencing does not affect cell viability or proliferation. When compared to the parental cell line, CMA-03/06 cells showed an activated pattern of the NF-κB pathway. This finding is supported by gene expression profiling (GEP) analysis identifying an appreciable fraction of modulated genes (28/308) in the CMA-03/06 subclone reported to be involved in this pathway. Furthermore, although more resistant to apoptotic stimuli compared to the parental cell line, CMA-03/06 cells display a higher sensibility to NF-κB inhibition induced by bortezomib. Finally, GEP analysis suggests an involvement of a number of cytokines, which might contribute to IL-6 independence of CMA-03/06 by stimulating growth and antiapoptotic processes. In conclusion, the parental cell-line CMA-03 and its variant CMA-03/06 represent a suitable model to further investigate molecular mechanisms involved in the IL-6-independent growth of myeloma cells. |
DOI | 10.1002/gcc.22127 |
Alternate Journal | Genes Chromosomes Cancer |
PubMed ID | 24327544 |
Related Faculty:
Giorgio Inghirami, M.D.