Identification of Genes Associated with Increased Bone Marrow Angiogenesis in Multiple Myeloma.

Introduction: Increased bone marrow angiogenesis is a characteristic feature of multiple myeloma (MM) and correlates with disease progression. Increased bone marrow angiogenesis at the time of diagnosis, measured in terms of microvessel density (MVD), is a powerful adverse prognostic factor for patients with MM. To better understand the biological basis of this phenomenon and to understand the mechanisms responsible for increased MVD in MM we compared the gene expression profiles of plasma cells from newly diagnosed MM patients with low and high MVD. Methods: Bone marrow biopsy sections from pts with newly diagnosed MM were studied using CD34 immunostaining and graded as low, intermediate, or high by MVD as previously described. 19 pts each, with low or high MVD were included for this study. RNA was isolated from CD138+ plasma cells of MM patients and analyzed using Affymetrix HG-U133A arrays. To examine differential expression, GC-RMA normalized data was analyzed using GeneSpring 7.2 software and genes with ≥ 2-fold differential expression between high and low MVD samples were identified. The Welch T-test was used to determine the significance of differential expression. Results and Conclusion: Expression of 42 transcripts was increased ≥ 2-fold in samples with high MVD in comparison to samples with low MVD. Of these transcripts, 14 were found to be significantly increased (P<0.05) using the Welch T-test (see Table 1). Expression of 16 transcripts was decreased ≥ 2-fold in samples with high MVD in comparison to samples with low MVD. Of these transcripts, 6 were found to be significantly decreased (P<0.05) using the Welch T-test (see Table 1). Genes differentially expressed include those involved in inhibiting apoptosis, facilitating IL-6 signaling, ion transport, extracellular matrix interaction, and regulating gene expression. Classical angiogenesis genes including VEGF, FGF, and IGF were not found to be differentially expressed (> 2-fold). In conclusion, the list of differentially expressed genes reveals many functions relevant to MM disease pathology including proliferation, apoptosis, regulation of gene expression, cytokine signaling, and adhesion. Current studies evaluating the expression and function of these genes in relation to MM may identify factors critical for angiogenesis and MM progression and provide insight for therapeutic intervention. Gene Description Fold Change COL1A2 collagen, type I, alpha 2 3.008 MCL1 myeloid cell leukemia sequence 1 (BCL2-related) 2.793 209183_s_at chromosome 10 open reading frame 10 2.541 VIL2 villin 2 2.478 IL6ST interleukin 6 signal transducer (gp130) 2.404 CLIC2 chloride intracellular channel 2 2.364 DEPDC6 DEP domain containing 6 2.35 PBXIP1 pre-B-cell leukemia transcription factor interacting protein 1 2.337 CLIC4 chloride intracellular channel 4 2.334 CYP51A1 cytochrome P450, family 51, subfamily A, polypeptide 1 2.095 LIMS1 LIM and senescent cell antigen-like domains 1 2.091 YWHAE tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide 2.042 OAS1 2′,5′-oligoadenylate synthetase 1, 40/46kDa 2.031 S100A11 S100 calcium binding protein A11 2.018 222378_at unknown transcribed sequences 0.496 SLC5A3 mitochondrial ribosomal protein S6 0.463 213089_at unknown transcribed sequences 0.406 PDE4B phosphodiesterase 4B, cAMP-specific 0.454 SVIL supervillin 0.386 RIPX rap2 interacting protein x 0.383