DLBCL-associated NOTCH2 mutants promote resistance to CHOP therapy. (A) 1 × 10⁷ U2932 cells stably expressing the indicated NOTCH2 cDNA were xenografted in the flanks of NSG mice. After the average tumor volumes reached 100 mm³, mice were treated with cyclophosphamide (30 mg/kg), doxorubicin (2.48 mg/kg), and vincristine (0.38 mg/kg) IV on day 1, and prednisone (0.2 mg/kg) was given via oral gavage daily for 5 days. The experimental end point was reached when the tumor volume reached 1000 mm³. Each line represents one tumor in one mouse (n = 5 per group, two-way ANOVA). (B) Kaplan-Meier survival analysis of mice shown in panel A (n = 5 per group; Mantel-Cox test). (C) Principal component analysis for the transcriptomes of tumors with the indicated genotypes. (D) Volcano plot representing the log₂ (fold change) over the -log₁₀ (P value) of the differentially expressed genes. The red circles represent the significantly upregulated genes, and the blue circles represent the significantly downregulated genes (n = 3; DeSeq2; P ≤ .01). (E) Dot plot showing the GSEA for the transcriptomes in (D). The size of the dots is a function of the P value; the color represents the normalized enrichment score. (F) Heat map showing the relative expression of KRAS-activated and P53-repressed signature genes using the normalized counts from the transcriptome analysis in panel D.