Figure 3.
Identification and validation of the MM progression signature. (A) Differential expression analysis was performed by comparing samples from distant BM sites and primary sites in MM.1S model using DESeq2 (FDR <5%). Differentially expressed genes were defined by an FDR cutoff of 5%, as indicated by the horizontal dashed line. The top 300 up- or downregulated genes with highest significance were defined as a progression signature, highlighted in blue (downregulated) or red (upregulated). (B) Association of the progression signature to MM progression and relapse. A Z score was used to quantify the enrichment level of the signature for each gene expression profile in data set GSE6477 (see “Methods”). Distributions were compared between MM stages during disease progression to healthy donors, using Wilcoxon rank sum test. Number of samples in each group and P values are shown. (C) Association of the progression signature to MM progression and aggressive disease. A Z score was used to quantify the enrichment level of the signature for each gene expression profile in data set GSE2113. Distributions were compared between MM stages during disease progression, using Wilcoxon rank sum test. Number of samples in each group and P values are also shown. (D) The progression signature acts as a predictor of overall survival in MM patients. Using a public data set of patient gene expression (GSE24080), the top 200 patients with the highest enrichment of progression signature were defined as a high-risk group, while those with the lowest enrichment were defined as a low-risk group. Statistical comparison was performed by log-rank test. (E) Pathway enrichment analysis of differentially expressed genes in MM.1S model. R package was used to assess significance of KEGG pathways. Top repressed or activated pathways were shown in green or red, respectively. The full list of significant pathways can be found in supplemental Table 5. CI, confidence interval; HR, hazard ratio; MAPK, mitogen activated protein kinase; NC, negative control; NewMM, newly diagnosed MM; PCL, plasma cell leukemia; R, receptor; ReMM, relapsed MM; SmMM, SMM.

Identification and validation of the MM progression signature. (A) Differential expression analysis was performed by comparing samples from distant BM sites and primary sites in MM.1S model using DESeq2 (FDR <5%). Differentially expressed genes were defined by an FDR cutoff of 5%, as indicated by the horizontal dashed line. The top 300 up- or downregulated genes with highest significance were defined as a progression signature, highlighted in blue (downregulated) or red (upregulated). (B) Association of the progression signature to MM progression and relapse. A Z score was used to quantify the enrichment level of the signature for each gene expression profile in data set GSE6477 (see “Methods”). Distributions were compared between MM stages during disease progression to healthy donors, using Wilcoxon rank sum test. Number of samples in each group and P values are shown. (C) Association of the progression signature to MM progression and aggressive disease. A Z score was used to quantify the enrichment level of the signature for each gene expression profile in data set GSE2113. Distributions were compared between MM stages during disease progression, using Wilcoxon rank sum test. Number of samples in each group and P values are also shown. (D) The progression signature acts as a predictor of overall survival in MM patients. Using a public data set of patient gene expression (GSE24080), the top 200 patients with the highest enrichment of progression signature were defined as a high-risk group, while those with the lowest enrichment were defined as a low-risk group. Statistical comparison was performed by log-rank test. (E) Pathway enrichment analysis of differentially expressed genes in MM.1S model. R package was used to assess significance of KEGG pathways. Top repressed or activated pathways were shown in green or red, respectively. The full list of significant pathways can be found in supplemental Table 5. CI, confidence interval; HR, hazard ratio; MAPK, mitogen activated protein kinase; NC, negative control; NewMM, newly diagnosed MM; PCL, plasma cell leukemia; R, receptor; ReMM, relapsed MM; SmMM, SMM.

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