title: Molecular events underlying interleukin-6 independence in a subclone of the CMA-03 multiple myeloma cell line.
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.
authors: Department of Clinical Sciences and Community Health, University of Milano and Hematology-CTMO, Fondazione Cà Granda, IRCCS Policlinico, Milano, Italy.
authors: Donata
authors: D
authors: Verdelli
authors: Lucia
authors: L
authors: Nobili
authors: Katia
authors: K
authors: Todoerti
authors: Laura
authors: L
authors: Mosca
authors: Sonia
authors: S
authors: Fabris
authors: Marianna
authors: M
authors: D'Anca
authors: Elisa
authors: E
authors: Pellegrino
authors: Roberto
authors: R
authors: Piva
authors: Giorgio
authors: G
authors: Inghirami
authors: Chiara
authors: C
authors: Capelli
authors: Martino
authors: M
authors: Introna
authors: Luca
authors: L
authors: Baldini
authors: Raffaella
authors: R
authors: Chiaramonte
authors: Luigia
authors: L
authors: Lombardi
authors: Antonino
authors: A
authors: Neri
mesh_terms: D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D001897:Boronic Acids; D015850:Interleukin-6; D016328:NF-kappa B; D011719:Pyrazines; D000069286:Bortezomib