Targeted metabolic and transcriptomic analysis of patients-derived T-ALL cells. (A) Principal component analysis of 8 PDXs undergoing targeted metabolomic analysis. (B) Most upregulated and downregulated metabolites in PTEN-altered cases. (C-D) Heat maps of the most 50 deregulated metabolites (C) and pathways enriched in PTEN-altered patients (D). (E) Metabolic analysis of citrate, CoA, acetyl-CoA, glutamine, glutamate, α-ketoglutarate, palmitic acid, stearic acid, and oleic acid in the 8 PDXs shown in panel A. (F) Venn diagram for metabolites mostly changed in both PTEN-mutant mice and PTEN-altered PDX (P < .05). (G) Metabolic transcriptome-based clustering of 155 patients. (H) Pathway enrichment analyses based on the differential metabolic gene expression of PTEN-altered (n = 33) vs wild-type (WT; n = 122) patients determined using EnrichR. (I) PROGENy score computation from whole transcriptomics data from 155 patients. The median score of the series was used to stratify patients into high- and low-score groups. (J) Volcano plot depicting differentially expressed metabolic genes in high vs low PI3K score. (K-L) Enriched metabolic gene sets enrichment in high vs low PI3K score as determined by GSEA. (M) Intracellular levels of cholesterol in WT or altered PI3K signaling T-ALL PDX blasts. Adj, adjusted; ADP, adenosine diphosphate; ALT, altered; CDP, cytidine diphosphate; FDR, false discovery rate; GSEA, gene set enrichement analysis; GDP, guanosine diphosphate; GTP, guanosine triphosphate; ns, not significant; PIP, phosphatidylinositol; tRNA, transfer RNA; UDP, uridine diphosphate.