Figure 3.
Subclone-specific adaptation mechanisms to treatment reflect the clonal evolution pattern. (A) (Left) Percentage of differentially expressed genes between T1 and T2 that are shared across subclones of the same patient (Padj ≤ .05; 1.5-fold enrichment both ways; Wilcoxon rank sum test). (Right) Percentage of TF motif activity changes between T1 and T2 (Padj ≤ .05) that are shared across subclones of the same patient. Motif deviation scores were calculated based on all differential peaks, with Padj ≤ .05 and 1.5-fold enrichment (Wilcoxon rank sum test). (B,E,H) Bar plot depicting the subclone frequency of patients (B) RRMM7, (E) RRMM3, and (H) RRMM9 and time points (T1/T2) based on scATAC-seq data. Individual stacks are colored according to the respective subclone identity. (C,F,I) Gene expression changes for patients (C) RRMM7, (F) RRMM3, and (I) RRMM9 across subclones from T1 to T2. Color indicates pseudobulk gene expression of the differentially expressed genes between T1 and T2 (Padj ≤ .05; RRMM3+7: 1.5-fold enrichment both ways, RRMM9: log2-fold change >0.25 both ways; Wilcoxon rank sum test). (Left) Heatmap of scRNA-seq pseudobulk expression across subclones and timepoints. Significant (C) HSPs or (F,I) genes of the NF-κB pathway commonly upregulated in all subclones that have previously been described in the context of drug resistance are labelled. (Right) Violin plots showing normalized gene expression per time point and subclone for HSPs or genes belonging to the NF-κB pathway. (D,G,J) Epigenetic changes for patients (D) RRMM7, (G) RRMM3, and (J) RRMM9 across subclones from T1 to T2. Color indicates pseudobulk TF motif activity of the top 50 most highly variable TFs (plus NF-κB TFs motifs for RRMM9). (Left) Heatmap of the top 50 of 54 TF motifs, which show a significant higher or lower motif deviation score at relapse (T2) compared with that at T1. (D) TFs putatively binding to the HSPs promoter or (G,J) TFs from the NF-κB family commonly upregulated in both subclones are labelled. (Right) Violin plots showing scATAC-seq TF motif activity per time point and subclone for 2 or 3 exemplary TFs.

Subclone-specific adaptation mechanisms to treatment reflect the clonal evolution pattern. (A) (Left) Percentage of differentially expressed genes between T1 and T2 that are shared across subclones of the same patient (Padj ≤ .05; 1.5-fold enrichment both ways; Wilcoxon rank sum test). (Right) Percentage of TF motif activity changes between T1 and T2 (Padj ≤ .05) that are shared across subclones of the same patient. Motif deviation scores were calculated based on all differential peaks, with Padj ≤ .05 and 1.5-fold enrichment (Wilcoxon rank sum test). (B,E,H) Bar plot depicting the subclone frequency of patients (B) RRMM7, (E) RRMM3, and (H) RRMM9 and time points (T1/T2) based on scATAC-seq data. Individual stacks are colored according to the respective subclone identity. (C,F,I) Gene expression changes for patients (C) RRMM7, (F) RRMM3, and (I) RRMM9 across subclones from T1 to T2. Color indicates pseudobulk gene expression of the differentially expressed genes between T1 and T2 (Padj ≤ .05; RRMM3+7: 1.5-fold enrichment both ways, RRMM9: log2-fold change >0.25 both ways; Wilcoxon rank sum test). (Left) Heatmap of scRNA-seq pseudobulk expression across subclones and timepoints. Significant (C) HSPs or (F,I) genes of the NF-κB pathway commonly upregulated in all subclones that have previously been described in the context of drug resistance are labelled. (Right) Violin plots showing normalized gene expression per time point and subclone for HSPs or genes belonging to the NF-κB pathway. (D,G,J) Epigenetic changes for patients (D) RRMM7, (G) RRMM3, and (J) RRMM9 across subclones from T1 to T2. Color indicates pseudobulk TF motif activity of the top 50 most highly variable TFs (plus NF-κB TFs motifs for RRMM9). (Left) Heatmap of the top 50 of 54 TF motifs, which show a significant higher or lower motif deviation score at relapse (T2) compared with that at T1. (D) TFs putatively binding to the HSPs promoter or (G,J) TFs from the NF-κB family commonly upregulated in both subclones are labelled. (Right) Violin plots showing scATAC-seq TF motif activity per time point and subclone for 2 or 3 exemplary TFs.

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