Page 201 - Haematologica March 2020

Venetoclax response and maturation stage in AML
AB
CD
EF
Full list in Online Supplementary Table S6
Figure 5. Cell differentiation is associated with low BCL2 expression and venetoclax ex vivo resistance. (A) Heatmap of the median gene expression for each French- British-American (FAB) class and control samples are shown for BCL2 family genes in the Hemap acute myeloid leukemia (AML) data set. Sample groups are ordered based on the differentiation state between HSC and healthy monocytes. Z-scores were used to define high and low expression categories. Z-scores were further dis- cretized to low and high categories, defined as having Z-score cutoff over 2 for high and less than -2 for low expression. P-values for FAB subgroup comparisons are presented in the Online Supplementary Table S5. Similar analysis for TCGA data set is presented in the Online Supplementary Figure S6. (B) Heatmap of the median gene expression of BCL2 family genes for healthy hematopoietic cell types using Differentiation Map data set. (C) Significant BCL2, MCL1 or BCL-xL gene expression differences between samples with MLL, CBFB-MYH11 or RUNX1-RUNX1T1 fusion genes when compared to non-fusion gene containing samples in FAB M2 and M4 groups. Values obtained from the Hemap data set. *P-value<0.05, **P-value<0.001. (D) Pathway enrichment results with normalized enrichment score (NES) and significance as false discovery rate (FDR) q-value are shown for pathways upregulated in M4 and M5 samples when compared to M0 and M1 samples. Pathways consistently enriched in both Hemap and TCGA data sets are shown here, while full results are shown in the Online Supplementary Table S6. (E) Heatmap of IL6- JAK-STAT3 signaling pathway leading edge gene expression Z-scores using the Hemap data set. Z-scores were further discretized to low and high categories, defined as having Z-score cutoff over 2 for high and less than -2 for low expression. Samples are ordered based on FAB type. (F) Venetoclax drug response AUC and IC50 profiles, BCL2 family genes and differentiation marker gene expression value Z-scores and FAB subtypes are shown as a heatmap. Samples are ordered based on drug sensitivity with sensitive samples on the left and resistant on the right. Pearson correlation Rho and FDR value is shown for each gene.
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