Fig. 4

Combination of imatinib and ISRIB reprogrammes the gene expression profile of primary TKI-resistant blasts. A Two-dimensional principal component analysis plot of samples based on gene expression (TPM) data obtained from FACS-sorted hCD45+ CML cells isolated from untreated control mice (n = 2, blue), or treated with ISRIB (n = 3, red), imatinib alone (n = 3, orange) or with combination of imatinib and ISRIB (n = 3, green). B Hierarchically clustered heatmap of fold-changes in expression (log2FoldChange) of significantly differentially expressed genes between the indicated pairs of conditions. Pairwise correlations of expression fold-changes are also shown. C Significantly altered genes upregulated (positive value on x-axis) or downregulated (negative value on x-axis) in combined imatinib and ISRIB treatment versus with imatinib alone. D Clusters (C0-C12) of co-expressed genes with varying patterns of gene expressions across all variants of treatment. Clusters C0, C1 displaying sharp downregulation or C5, C6 showing sharp upregulation of gene expression after combined treatment are marked in blue frame. E Diagram showing the percentage of genes identified in four selected clusters C0, C1, C5, C6 (blue) and the rest (grey). Transcriptome analysis has been done on hCD45+ cells isolated from BM respirates of PDX mouse model with CD34+ CML-BP imatinib resistant blasts carrying PTPN11 mutation