Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan

Because there is no known genetic abnormality common to all patients with m yeloma, it is important to understand how genetic heterogeneity may lead to differences in signal transduction, cell cycle, and response to therapy. M odel cell lines have been used to study the effect that mutations in p53 an d ras can have on growth properties and responses of myeloma cells, The U26 6 cell line has a single mutant p53 allele, Stable expression of wild-type (wt) p53 in U266 cells results in a significant suppression of interleukin (IL)-6 gene expression and in the concomitant suppression of cell growth th at could be restored by the addition of exogenous IL-6, Expression of wt p5 3 also leads to cell cycle arrest and protection from doxorubicin (Dox)- an d melphalan (Mel)-induced apoptosis, The addition of IL-6 resulted in cell cycle progression and blocked p53-mediated protection from apoptosis, ANBL6 is an IL-6-dependent cell line that is sensitive to dexamethasone (Dex), B ox, and Mel. IL-6 is able to protect ANBL6 cells from Dex- and Mel- but not Box-induced apoptosis, To study the effect of an activating mutation in ra s, the ANBL6 cell line transfected with either a constitutively activated N - or K-ras gene was used. Both N-ras12 and K-ras12 genes were able to prote ct ANBL6 cells from apoptosis induced by Dex, Box, and Mel. These data show that changes in ras or p53 can alter the myeloma cell response to IL-6 and demonstrate that the genetic background can alter therapeutic responses. ( C) 2000 by The American Society of Hematology.