Genetic heterogeneity between individuals confounds the comparison
of gene profiling of multiple myeloma (MM) cells versus normal
plasma cells (PCs). To overcome this barrier, we compared the
gene expression profile of CD138+ MM cells from a patient bone
marrow (BM) sample with CD138+ PCs from a genetically identical
twin BM sample using microarray profiling. Two hundred and ninety-six
genes were up-regulated and 103 genes were down-regulated at least
2-fold in MM cells versus normal twin PCs. Highly expressed genes
in MM cells included cell survival pathway genes such as mcl-1,
dad-1, caspase 8, and FADD-like apoptosis regulator (FLIP); oncogenes/transcriptional
factors such as Jun-D, Xbp-1, calmodulin, Calnexin, and FGFR-3;
stress response and ubiquitin/proteasome pathway-related genes
and various ribosomal genes reflecting increased metabolic and
translational activity. Genes that were down-regulated in MM cells
versus healthy twin PCs included RAD51, killer cell immunoglobulin-like
receptor protein, and apoptotic protease activating factor. Microarray
results were further confirmed by Western blot analyses, immunohistochemistry,
fluorescent in situ hybridization (FISH), and functional assays
of telomerase activity and bone marrow angiogenesis. This molecular
profiling provides potential insights into mechanisms of malignant
transformation in MM. For example, FGFR3, xbp-1, and both mcl-1
and dad-1 may mediate transformation, differentiation, and survival,
respectively, and may have clinical implications. By identifying
genes uniquely altered in MM cells compared with normal PCs in
an identical genotypic background, the current study provides
the framework to identify novel therapeutic targets.