In contrast, double-color fluorescence in situ hybridization analysis showed that BM-derived CD138-positive myeloma cells possessed the gene translocation between the immunoglobulin heavy chain gene and the cyclin D1 gene, which was not involved in non-myeloma hematopoietic cells.
Therefore, we assume that high sensitivity to anti-myeloma drugs depends on the duration of the S-phase, but a clinical response might depend on the number of myeloma cells with cyclin D1 overexpression.
Ribozyme cleavage leads to decreased expression of fibroblast growth factor receptor 3 in human multiple myeloma cells, which is associated with apoptosis and downregulation of vascular endothelial growth factor.
The study aim was to investigate Stat 3 activation in a series of multiple myeloma (MM) cases and its effect on downstream targets such as the anti-apoptotic proteins Bcl-xL, Mcl-1, and Bcl-2, and the cell-cycle protein cyclin D1.Forty-eight cases of MM were analyzed.
Strong cyclin D1 mRNA overexpression was detected in mantle cell lymphomas (23 of 23), hairy cell leukemias (5 of 19), and multiple myelomas (7 of 23) with particularly high levels in 2 of the latter cases.
As regards p16 methylation, we confirmed a high prevalence of p16 methylation (40%) in patients affected by MM and demonstrated that MTHFR 677CC is associated with a higher prevalence of p16 hypermethylation.
These findings showed methylation of the p16 gene was a frequent event inMM patients at diagnosis, and was associated with an increased proliferative rate of plasma cells and a poor prognosis, indicating an important role for p16 gene in the cell cycle regulation of multiple myeloma tumour cells, and thus in the clinical outcome of the disease.
Expression of BCMA, TACI, and BAFF-R by MM taken together with the ability of BLyS to support MM cell growth and survival has exciting implications because they may be potential therapeutic targets.
These data suggest that genetic variants of NHEJ LIG4 may modulate predisposition to multiple myeloma, a tumour characterised by aberrant immunoglobulin (Ig) class switch recombination.
To assess their etiologic role, we examined the association of 70 tagging single nucleotide polymorphisms (SNP) in seven IGF-1 and three IL-6 pathway genes with multiple myeloma risk in two prospective cohorts, the Nurses' Health Study and the Health Professionals Follow-up Study.
Using a combination of fluorescent in situ hybridization and comparative genomic hybridization arrays (aCGH), we have identified rearrangements of an MYC gene in 40 of 43 independent myeloma cell lines.
These findings indicate that MUC1 activates the beta-catenin and NF-kappaB pathways in multiple myeloma cells and contributes to their growth and survival.
In the search of an in vitro a model with molecular features similar to relapsing lesions, we focused our attention on an IL-6 autocrine human myeloma cell line (U266), characterized by apoptosis resistance due to upregulation of two constitutive signaling pathways: NFkappaB and STAT-3.
Treatment of IL-6-dependent and IL-6-independent multiple myeloma cell lines with CNTO 328 enhanced the cytotoxicity of bortezomib in a sequence-dependent fashion.
The IL-6 response of KAS-6/1 myeloma also raises a question of whether the proneoplastic growth factor, such as IL-6, supports the epigenetic silencing of important DNA repair genes via promoter hypermethylation during the development of multiple myeloma.
In conclusion, Mcl-1, which has been shown to be essential for the survival of human myeloma cells in vitro, is overexpressed in vivo in MM in relation with relapse and shorter survival.
In myeloma cells, we have previously shown that Mcl-1 neutralizes the proapoptotic function of Bim and therefore, prevents the activation of death effectors.
Conversely, stimulation with IL-6 enhanced bFGF expression and secretion by myeloma cell lines (2-fold; P =.02) as well as MM patient cells (up to 3.6-fold; median, 1.5-fold; P =.002).
Analysis of the transcriptional activity of 5'-regulatory sequences from the human Mcl-1 gene in MM cells demonstrated high levels of IL-6-independent indicator gene activation as predicted.