Genomic alterations of BCL2 members are linked to venetoclax resistance in t(11;14) MM. (A) Genome accessibility track visualization of MCL1 with peak-to-gene links identified by ArchR in the prevenetoclax and postvenetoclax therapy samples for each patient (PM01, PM07, PM09, and PM10). The color of the arcs indicates the correlation strength between the peak and the gene expression, with a darker color indicating a stronger correlation. The genes are indicated in red when the gene is on the positive strand (TSS on the left) and in blue when on the negative strand (TSS on the right). The gray boxes highlighted the enhancer or promoter regions of the gene of interest. (B) Boxplots indicating the BCL2/MCL1 gene expression ratios in the prevenetoclax and postvenetoclax samples of each patient with MM treated with venetoclax (PM01, PM07, PM09, and PM10). The FDR values of the comparison prevenetoclax vs postvenetoclax sample of each patient are shown at the top of each boxplot comparison. (C) Immunoblotting of parental (WT) and MCL1-overexpressing KMS12BM cells for the indicated BCL2 family members in the presence or absence of venetoclax 200 nM for 3 hours. (D) Bar plot showing the percentage of cell death observed in parental (WT) vs MCL1-KMS12BM cells after 24 hours of exposure to venetoclax 200 nM. The data presented are the mean ± standard error of 3 independent experiments. The adjusted P values associated are shown at the top of each bar plot. (E-G) Boxplots indicating the MCL1/PMAIP1 (E), PMAIP1 (F), and BCL2/BCL2L1 (G) gene expression ratios in the prevenetoclax and postvenetoclax samples for each patient (PM01, PM07, PM09, and PM10). The FDR values associated with the comparison of prevenetoclax vs postvenetoclax cells are shown at the top of each boxplot comparison. (H) Genome accessibility track visualization of BCL2L1 with peak-to-gene links identified by ArchR in the prevenetoclax and postvenetoclax samples for patient PM01. The color of the arcs indicates the correlation strength between the peak and the gene expression with a darker color indicating a stronger correlation. The genes are indicated in red when the gene is on the positive strand (TSS on the left) and in blue when on the negative strand (TSS on the right). The gray boxes highlight the enhancer or promoter regions of the gene of interest.

Genomic alterations of BCL2 members are linked to venetoclax resistance in t(11;14) MM. (A) Genome accessibility track visualization of MCL1 with peak-to-gene links identified by ArchR in the prevenetoclax and postvenetoclax therapy samples for each patient (PM01, PM07, PM09, and PM10). The color of the arcs indicates the correlation strength between the peak and the gene expression, with a darker color indicating a stronger correlation. The genes are indicated in red when the gene is on the positive strand (TSS on the left) and in blue when on the negative strand (TSS on the right). The gray boxes highlighted the enhancer or promoter regions of the gene of interest. (B) Boxplots indicating the BCL2/MCL1 gene expression ratios in the prevenetoclax and postvenetoclax samples of each patient with MM treated with venetoclax (PM01, PM07, PM09, and PM10). The FDR values of the comparison prevenetoclax vs postvenetoclax sample of each patient are shown at the top of each boxplot comparison. (C) Immunoblotting of parental (WT) and MCL1-overexpressing KMS12BM cells for the indicated BCL2 family members in the presence or absence of venetoclax 200 nM for 3 hours. (D) Bar plot showing the percentage of cell death observed in parental (WT) vs MCL1-KMS12BM cells after 24 hours of exposure to venetoclax 200 nM. The data presented are the mean ± standard error of 3 independent experiments. The adjusted P values associated are shown at the top of each bar plot. (E-G) Boxplots indicating the MCL1/PMAIP1 (E), PMAIP1 (F), and BCL2/BCL2L1 (G) gene expression ratios in the prevenetoclax and postvenetoclax samples for each patient (PM01, PM07, PM09, and PM10). The FDR values associated with the comparison of prevenetoclax vs postvenetoclax cells are shown at the top of each boxplot comparison. (H) Genome accessibility track visualization of BCL2L1 with peak-to-gene links identified by ArchR in the prevenetoclax and postvenetoclax samples for patient PM01. The color of the arcs indicates the correlation strength between the peak and the gene expression with a darker color indicating a stronger correlation. The genes are indicated in red when the gene is on the positive strand (TSS on the left) and in blue when on the negative strand (TSS on the right). The gray boxes highlight the enhancer or promoter regions of the gene of interest.

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