Extended Data Fig. 6: Biomarker model of dasatinib sensitivity in T-ALL.
a,b, A panel of 30 genes were selected as biomarkers from the top 461 driver genes in the NetBID analysis, as described in Methods. Dasatinib biomarker score was plotted for T-ALL cases, in the discovery cohort (a, N = 45) and in the validation cohort (b, N = 13). P value was estimated using two-tailed t test. c, Similarly, activity of each biomarker gene was estimated for the TARGET T-ALL cohort, from which an unsupervised clustering analysis was performed, as shown in the heatmap. Each row is a biomarker gene and each column represents a T-ALL case, with color discriminating the level of inferred gene activity. T-ALL subtype is indicated in the top row by color. d,e, Predicted LCK and PTCRA activity in the TARGET T-ALL cohort (N = 261). Activity of LCK and PTCRA was estimated for each T-ALL case from its RNA-seq data by NetBID algorithm. T-ALL subtypes were defined as previously described (Liu et al., 2017). f, In TARGET cohort, dasatinib biomarker score of cases in LMO2/LYL1 subtype showed a bimodal distribution. Cases with high biomarker score (dasatinib-sensitive, blue curve) exhibited a worse event-free survival compared to those with low biomarker score. P-value was estimated using Cox regression. g,h, Differential gene expression analyses of dasatinib sensitivity in T-ALL. In the discovery cohort, differences in gene expression between dasatinib-sensitive vs –resistant T-ALL was examined using the Limma method based on a linear model and results are presented as the volcano plot compared (g). Pathway analysis was performed with 254 genes that met the significance and effect size threshold (adjusted P < 1e-3 and log2 fold change >2), using the KEGG pathway database. P-value was inferred by Fisher exact test. I,j, Comparison of predicted dasatinib sensitivity in pediatric and adult T-ALL. i, Dasatinib biomarker score was significantly higher in pediatric cases than adults in the discovery cohort. This was also validated in an independent microarray-based T-ALL gene expression dataset (NCBI GSE32215) with 37 adult and 191 pediatric patient samples. j,T-ALL subtype was inferred from gene expression profile for cases in the GSE32215 dataset. Pediatric cases have a higher prevalence of the TAL1 and TAL2 subtypes whereas adults have a higher frequency of HOXA and LMO2/LYL1 subtypes. P value was estimated using two-tailed t test. Boxplots show summary of data in terms of the minimum, maximum, sample median, and the first and third quartiles.
