Introduction of an activated N-ras oncogene alters the growth characteristics of the interleukin 6-dependent myeloma cell line ANBL6.
Multiple myeloma (MM) is a late-stage B-cell cancer with an unknown etiology. Activating mutations of the N-ras and K-ras oncogenes occur with a high frequency in myeloma and, therefore, may play a role in the pathogenesis of the disease. To study the role of N-ras-activating mutations in the regulation of myeloma tumor growth, we introduced a constitutively active N-ras cDNA containing a glutamine to arginine (CAA-CGA) amino acid substitution at codon 61 into the interleukin 6 (IL-6)-dependent myeloma cell line ANBL6. Expression of the mutant N-ras cDNA resulted in significant IL-6-independent growth, as well as augmentation of growth at suboptimal concentrations of IL-6. The IL-6-independent growth pattern was not the result of activation of autocrine IL-6 production in the mutant N-ras-expressing population because neutralizing antibodies to the IL-6 receptor and to IL-6 had no effect on the rate of DNA synthesis in the absence of IL-6. Furthermore, mutant N-ras expression decreased the percentage of cells undergoing apoptosis in the absence of IL-6. These data suggest that activating mutations of the ras oncogenes may result in growth factor independence accompanied by a suppression of apoptosis in MM. Therefore, the use of therapies designed to block IL-6 action in MM may have less of an impact on tumors bearing activated ras mutations.
Billadeau
D
D
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
Jelinek
D F
DF
Shah
N
N
LeBien
T W
TW
Van Ness
B
B
D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D011905:Genes, ras; D006133:Growth Substances; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000473:pathology*; D017354:Point Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D006133:Growth Substances; D015850:Interleukin-6; D016283:Proto-Oncogene Proteins p21(ras)