Che-1 drives MM pathogenesis. (A) Overall survival in weeks of a cohort of 30 wild-type (WT) and 30 Vk*Che-1 mice. P value is shown. (B) Fluorescence-activated cell sorter analysis of the bone marrow (BM) from Vk*Che-1 transgenic mice and control littermates. Percentages of CD138⁺ cells are indicated. (C) Splenomegaly in Vk*Che-1 mice relative to age-matched nontransgenic littermate control mice. (D) Representative images of the spleen, liver, and kidney biopsy samples from Vk*Che-1 mice were analyzed by light microscopy (hematoxylin and eosin [H&E]) (left) and by immunohistochemical analysis for CD138⁺ positive cells (right) to reveal plasma cell infiltrates. Scale bar, 100 μm. (E) Boxplot showing the relative enrichment of differentially downregulated (left) and upregulated (right) ATAC-seq sites obtained from WT and Vk*Che-1 mice. X-axis: Sites split in downregulated (Down), not differential (Stable), and upregulated (Up) categories. Y-axis: Raw read counts normalized with the weighted trimmed mean of M-values (TMM). Color scheme: blue = WT; red = Vk*Che-1. (F) Heatmap of the top 10 significant enriched motifs in the Down and Up categories obtained from the ATAC-seq differential analysis (WT vs Vk*Che-1). Color proportional to the relative fold enrichment (observed/expected) of each motif in the 2 categories. Blue = WT; red = Vk*Che-1; white = not significant. All colored motifs exhibit a P < 10⁻¹⁰. (G) Heatmap of the top significant ontologies observed in the Down and Up categories. Entries are a compendium of the most significant Mouse Genome Informatics Phenotype⁵⁸  and Molecular Signature Database⁵⁹  pathway ontologies. Color proportional to the relative significance of each entry in the 2 categories. Blue = WT; red = Vk*Che-1. P < 10⁻⁵ from the hypergeometric test. (H) Top: Differential analysis of WT vs Vk*Che-1 transcriptome. Volcano plot shows 2507 significantly upregulated (red) and 2009 downregulated (blue) genes. x-axis: B value, which is an approximation of fold change obtained from the Wald test. y-axis: -log10 (false discovery rate [FDR]) of significant genes. Bottom: Gene Set Enrichment Analysis (GSEA) of upregulated (right) and downregulated (left) significant differential genes with associated legend to interpret the color scheme. See also supplemental Figure 5. FITC, fluorescein isothiocyanate; TF, transcription factor.