In vivo changes in gene expression profiles (GEP) after bortezomib (V) for multiple myeloma (MM): Differential effects on plasma cells (PC) and micro-environment (ME)

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7603 Introduction: V, a proteasome inhibitor with potent anti-myeloma activity, is thought to act through effects on malignant PC and the ME. However, the in vivo effects of this drug have never been examined at the molecular level. Methods: Serial GEP analyses were performed of paired purified PC and bone marrow biopsies from 46 patients, obtained prior to and 48hr following administration of a single V dose at 1mg/m2. RNA was isolated from whole biopsies and purified PCs from each sample, converted to cRNA, and hybridized to Affymetrix U133 Plus2 microarrays. SAM analysis with 5% false discovery rate was employed to identify drug-altered genes. Results: Following V, 36 ME-associated genes (MAGs) were up-regulated, among them the osteoinductive factor osteoglycin (OGN), consistent with a V effect on osteoblastogenesis; CYR61, an angiogenesis inducer, significantly over-expressed in myeloma relative to normal marrow, was one of only 3 significantly down-regulated genes. V is known to induce expression of proteasome genes and PSMA6, PSMA1, and PSMA14 were among 15 genes up-regulated in PC. In contrast, early growth response (EGR1, EGR2, and EGR3), Krupple-like factor (KLR4, KLR5, KLR6, and KLR7) and nuclear receptor (NR4A1, NR4A2, and NR4A3) family members were down-regulated in PC by V. These differential PC and ME expression changes were only noted in low-risk MM, lacking over-expression of CKS1B. Conclusion: We report here, for the first time, on the differential molecular consequences of a single in-vivo dose of V on both tumor cells and cells of the microenvironment. The clinical implications of these findings are being further investigated and will be presented. [Table: see text]