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

• Published in: Blood Vol. 96; no. 9; pp. 3175 - 3180
• Main Authors: Rowley, Matt, Liu, Pocheng, Van Ness, Brian
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.11.2000; The Americain Society of Hematology
• Subjects: Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Cell Cycle - drug effects; Chemotherapy; Dexamethasone - toxicity; Doxorubicin - toxicity; Gene Expression Regulation, Neoplastic - drug effects; Genes, p53; Genes, ras; Humans; Hydroxymethylbilane Synthase - genetics; Interleukin-6 - genetics; Interleukin-6 - pharmacology; Medical sciences; Melphalan - toxicity; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Mutation; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Antineoplastic agent; Human; Immunopathology; Corticosteroid; Dexamethasone; Steroid hormone; Cytokine; Antiinflammatory agent; Malignant hemopathy; Myeloma; Doxorubicin; Biological activity; Interleukin 6; Alkylating agent; TP53 Gene; Sensitivity resistance; Immunoglobulinopathy; Lymphoproliferative syndrome; Established cell line; Melphalan; Anthracyclins; Mutation; Ras gene
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V96.9.3175

Because there is no known genetic abnormality common to all patients with myeloma, it is important to understand how genetic heterogeneity may lead to differences in signal transduction, cell cycle, and response to therapy. Model cell lines have been used to study the effect that mutations in p53 and rascan have on growth properties and responses of myeloma cells. The U266 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 that could be restored by the addition of exogenous IL-6. Expression of wt p53 also leads to cell cycle arrest and protection from doxorubicin (Dox)- and 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), Dox, and Mel. IL-6 is able to protect ANBL6 cells from Dex- and Mel- but not Dox-induced apoptosis. To study the effect of an activating mutation in ras, the ANBL6 cell line transfected with either a constitutively activated N- orK-ras gene was used. Both N-ras12 andK-ras12 genes were able to protect ANBL6 cells from apoptosis induced by Dex, Dox, and Mel. These data show that changes inras or p53 can alter the myeloma cell response to IL-6 and demonstrate that the genetic background can alter therapeutic responses.