Figure 3.
High BCL-XL expression in erythroid and megakaryoblastic leukemia underlies sensitivity to BCL-XL inhibition. (A) Protein levels of BCL-2 family members of BCL-XL, BCL-2, and MCL-1 in 21 AML cell lines. FAB subtype, expression of BCL-2 family genes and erythroid lineage TFs in AML cell lines from the CCLE data set (gray color, data not available), drug sensitivity scores of BCL-2 family inhibitors, and TP53 mutations are shown below as heatmaps. (B) Sensitivity of parental (TP53 WT) and CRISPR-mediated TP53 knockout (TP53 KO) variants of MOLM13, MV411, and OCIAML2 cell lines to A-1331852 and venetoclax as drug sensitivity scores. Erythroid/megakaryocytic AML cell lines are shown as a comparison. P values were obtained using paired Welch t tests (KO vs WT) and Wilcoxon rank-sum tests (M6/M7 vs others). Bar heights indicate mean, error bars indicate standard deviation, and dots indicate individual cell lines. (C) Expression of BCL-2 family genes in AML FAB subtypes in the TCGA data set. In the box plot, the horizontal line indicates the median, boxes indicate the interquartile range, and whiskers extend from the hinge to the smallest/largest value, at most 1.5 interquartile range from the hinge. (D) BCL2L1 (BCL-XL) expression across hematological malignancies in the Hemap data set. P value for AML M6 samples compared with all other samples using Wilcoxon rank-sum test is shown. Box plot as in panel C. (E) UMAP plots of single-cell RNA-seq data of normal hematopoiesis from the HCA, with cell type annotations based on the reference-based method SingleR and BCL2L1, BCL2, and MCL1 expression levels as normalized and scaled log-transformed counts colored on the plots. (F) Colony-forming potential of healthy BM mononuclear cells after 24 hours pretreatment of the indicated compounds in cell culture. Each dot represents a technical replicate and number of colonies were normalized to control after culturing the cells for 2 weeks in semisolid medium. Bar heights indicate mean and error bars indicate range. HCA, Human Cell Atlas; KO, knockout; WT, wild-type.

High BCL-XL expression in erythroid and megakaryoblastic leukemia underlies sensitivity to BCL-XL inhibition. (A) Protein levels of BCL-2 family members of BCL-XL, BCL-2, and MCL-1 in 21 AML cell lines. FAB subtype, expression of BCL-2 family genes and erythroid lineage TFs in AML cell lines from the CCLE data set (gray color, data not available), drug sensitivity scores of BCL-2 family inhibitors, and TP53 mutations are shown below as heatmaps. (B) Sensitivity of parental (TP53 WT) and CRISPR-mediated TP53 knockout (TP53 KO) variants of MOLM13, MV411, and OCIAML2 cell lines to A-1331852 and venetoclax as drug sensitivity scores. Erythroid/megakaryocytic AML cell lines are shown as a comparison. P values were obtained using paired Welch t tests (KO vs WT) and Wilcoxon rank-sum tests (M6/M7 vs others). Bar heights indicate mean, error bars indicate standard deviation, and dots indicate individual cell lines. (C) Expression of BCL-2 family genes in AML FAB subtypes in the TCGA data set. In the box plot, the horizontal line indicates the median, boxes indicate the interquartile range, and whiskers extend from the hinge to the smallest/largest value, at most 1.5 interquartile range from the hinge. (D) BCL2L1 (BCL-XL) expression across hematological malignancies in the Hemap data set. P value for AML M6 samples compared with all other samples using Wilcoxon rank-sum test is shown. Box plot as in panel C. (E) UMAP plots of single-cell RNA-seq data of normal hematopoiesis from the HCA, with cell type annotations based on the reference-based method SingleR and BCL2L1, BCL2, and MCL1 expression levels as normalized and scaled log-transformed counts colored on the plots. (F) Colony-forming potential of healthy BM mononuclear cells after 24 hours pretreatment of the indicated compounds in cell culture. Each dot represents a technical replicate and number of colonies were normalized to control after culturing the cells for 2 weeks in semisolid medium. Bar heights indicate mean and error bars indicate range. HCA, Human Cell Atlas; KO, knockout; WT, wild-type.

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