Figure 3.
Loss of B-cell–like epigenetic signature with gain of canonical PC TFs is associated with acquired resistance to venetoclax in t(11;14) MM. (A-B) UMAP projection showing the distribution of CD138+ cells (n = 26 847 cells) collected from 4 patients with t(11;14) MM using the scATAC-seq and scRNA-seq data in the LSI space. Each point represents 1 cell. The cells are marked by a color code based on the different patient (A) and treatment (before vs after venetoclax) (B). (C) Odds ratios indicating the overlap of the DAR identified in the pre- (light blue) and post- (purple) venetoclax MM cells when compared with those present in the MB cells and PCs. The error bars denote the 95% confidence interval calculated using a two-sided Fisher exact test. (D) Violin plots of the NES obtained in the prevenetoclax vs postvenetoclax MM cells. These data were generated on the integrated scRNA-seq counts using the msigdb for BM PCs (C8, HAY_BONE_MARROW_PLASMA_CELL) and B cells (C8, HAY_BONE_MARROW_FOLLICULAR_B_CELL). (E-F) Violin plots of the NES obtained in the prevenetoclax vs postvenetoclax MM cells in each paired patient treated with venetoclax (PM01, PM07, PM09, and PM10). These data were generated on the integrated scRNA-seq counts using the msigdb for BM PCs (E) (C8, HAY_BONE_MARROW_PLASMA_CELL) and B cells (F) (C8, HAY_BONE_MARROW_FOLLICULAR_B_CELL). (G) Heat map of the motif hypergeometric enrichment-adjusted P values within the Catalog of Inferred Sequence Binding Preferences databases of each prevenetoclax and postvenetoclax MM cell from patients PM01, PM07, PM09, and PM10. The color indicates the motif enrichment (−log10[P value]) based on the hypergeometric test. The maximum mlog10Padj is indicated in parenthesis for each significant enrichment found. (H) Representation of the Tn5 bias–adjusted TF footprints for IRF4, RUNX1, ID3, and TCF4 motifs identified by the enrichment motif analysis. The lines are colored in blue and red to indicate the prevenetoclax and postvenetoclax samples for patient PM01 and in purple and green for patient PM07.

Loss of B-cell–like epigenetic signature with gain of canonical PC TFs is associated with acquired resistance to venetoclax in t(11;14) MM. (A-B) UMAP projection showing the distribution of CD138+ cells (n = 26 847 cells) collected from 4 patients with t(11;14) MM using the scATAC-seq and scRNA-seq data in the LSI space. Each point represents 1 cell. The cells are marked by a color code based on the different patient (A) and treatment (before vs after venetoclax) (B). (C) Odds ratios indicating the overlap of the DAR identified in the pre- (light blue) and post- (purple) venetoclax MM cells when compared with those present in the MB cells and PCs. The error bars denote the 95% confidence interval calculated using a two-sided Fisher exact test. (D) Violin plots of the NES obtained in the prevenetoclax vs postvenetoclax MM cells. These data were generated on the integrated scRNA-seq counts using the msigdb for BM PCs (C8, HAY_BONE_MARROW_PLASMA_CELL) and B cells (C8, HAY_BONE_MARROW_FOLLICULAR_B_CELL). (E-F) Violin plots of the NES obtained in the prevenetoclax vs postvenetoclax MM cells in each paired patient treated with venetoclax (PM01, PM07, PM09, and PM10). These data were generated on the integrated scRNA-seq counts using the msigdb for BM PCs (E) (C8, HAY_BONE_MARROW_PLASMA_CELL) and B cells (F) (C8, HAY_BONE_MARROW_FOLLICULAR_B_CELL). (G) Heat map of the motif hypergeometric enrichment-adjusted P values within the Catalog of Inferred Sequence Binding Preferences databases of each prevenetoclax and postvenetoclax MM cell from patients PM01, PM07, PM09, and PM10. The color indicates the motif enrichment (−log10[P value]) based on the hypergeometric test. The maximum mlog10Padj is indicated in parenthesis for each significant enrichment found. (H) Representation of the Tn5 bias–adjusted TF footprints for IRF4, RUNX1, ID3, and TCF4 motifs identified by the enrichment motif analysis. The lines are colored in blue and red to indicate the prevenetoclax and postvenetoclax samples for patient PM01 and in purple and green for patient PM07.

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