Expression of Nuclear Factor-kappa B Pathway Genes and Their Correlation with Clinical Features in Multiple Myeloma.

Abstract

NF-k B is a transcription factor that controls the expression of a variety of genes involved in different cellular processes, including apoptosis regulation, cell proliferation and expression of adhesion molecules. In multiple myeloma (MM) patients, NF-k B confers longer survival and drug resistance to tumor cells. Therefore, a better understanding of molecular mechanisms involved in NF-k B pathway can contribute to identify new therapeutic targets for this incurable disease.Purpose: To evaluate the expression of NF-k B pathway genes in MM patients by real-time quantitative PCR and its possible correlation with disease clinical features and survival.Patients and methods: Expression of eight genes related to NF-k B pathway (NFKB, IKB, RANK, RANKL, OPG, IL6, VCAM and ICAM) were studied in 53 bone marrow samples from newly diagnosed MM patients and in seven normal controls, using Taqman system. Genes were considered overexpressed when tumor expression level was at least four times higher than the observed in normal samples. These results were compared to clinical variables using Pearson's Qui-square and T-Test. Overall survival (OS) was estimated using Kaplan-Meier method.Results: 18.9% of MM cases were classified as ISS 1, 34% ISS 2 and 39.6% ISS 3. The percentages of overexpression of the eight genes were: NFKB 0%, IKB 22.6%, RANK 15.1%, RANKL 31.3%, OPG 7.5%, IL6 39.6%, VCAM 10% and ICAM 26%. We found association between IL6 expression level and the International Staging System (ISS) (p = 0.01), meaning that MM patients with high ISS scores have more chance of overexpression of IL6. We also found association between IL6 overexpression and presence of chromosome 13 deletion (p= 0.035), a well-known marker of worse prognosis in MM. Mean value of ICAM relative expression was also associated with ISS score (p = 0.02). Regarding OS, cases with IL6 overexpression present worse evolution than cases with IL6 normoexpression (p=0.04).Conclusions: IL6 overexpression was found in 39.6% of MM cases and confirms its participation in myeloma progression, regulating growth and survival of tumor cells. Besides, IL6 overexpression was significantly associated with advanced stage disease and del(13) and had impact on MM patient's survival. ICAM was overexpressed in 26% of cases and its level was associated with ISS scores. Therefore, ICAM seems to have some potential as therapeutic target in MM.