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

Abstract

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.GeneDescriptionFold ChangeCOL1A2collagen, type I, alpha 23.008MCL1myeloid cell leukemia sequence 1 (BCL2-related)2.793209183_s_atchromosome 10 open reading frame 102.541VIL2villin 22.478IL6STinterleukin 6 signal transducer (gp130)2.404CLIC2chloride intracellular channel 22.364DEPDC6DEP domain containing 62.35PBXIP1pre-B-cell leukemia transcription factor interacting protein 12.337CLIC4chloride intracellular channel 42.334CYP51A1cytochrome P450, family 51, subfamily A, polypeptide 12.095LIMS1LIM and senescent cell antigen-like domains 12.091YWHAEtyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide2.042OAS12′,5′-oligoadenylate synthetase 1, 40/46kDa2.031S100A11S100 calcium binding protein A112.018222378_atunknown transcribed sequences0.496SLC5A3mitochondrial ribosomal protein S60.463213089_atunknown transcribed sequences0.406PDE4Bphosphodiesterase 4B, cAMP-specific0.454SVILsupervillin0.386RIPXrap2 interacting protein x0.383