The recent development of gene expression profiling has highlighted the sequential genetic change from normal plasma cell to a malignant one. The transformation of MGUS to MM provides an opportunity to better understand the genes involved and correlates these molecular changes with various environmental events. Recently, microarray analysis of plasma cells from 5 healthy donors, 7 patients with MGUS, and 24 MM patients established 380 genes differentially expressed between normal and MM, but a much smaller difference of only 74 genes that were differentially expressed between MGUS and MM samples. Differentially expressed genes included oncogenes/tumor-suppressor genes (LAF4, RB1, and disabled homolog 2), cell-signaling genes (RAS family members, B-cell signaling, and NF-kB genes), DNA-binding and transcription-factor genes (XBP1, zinc-finger proteins, forkhead box, and ring-finger proteins), and developmental genes (WNT and SHH pathways).161 In a twin experiment, gene profiling of MM cells allows us to overcome the individual genetic heterogeneity. A recent study compared the gene expression profile of MM cells from a patient's bone marrow with his genetically identical healthy twin. Two hundred and ninety-six genes were upregu-lated and 103 genes were downregulated at least twofold in MM cells versus the normal twin plasma cells (PCs). Highly expressed genes in MM cells included cell survival pathway genes such as mcl-1, dad-1, cas-pase 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. Several genes were downregulated in MM cells versus healthy twin PCs including RAD51, killer cell immunoglobulin-like receptor protein, and apoptotic protease activating factor. This study provides insights into the mechanisms involved in malignant transformation in MM.162 These new developments of the molecular mechanisms of MM will help us understand what causes the disease and develop effective preventive and treatment strategies.
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