Fig. 1
A-C: Anti-NOTCH1 (OMP-52M51) inhibits growth of NOTCH1-driven relapsed T-ALL PDXs. NSG mice (n = 5 mice/group) were i.p. treated with OMP-52M51 (anti-N1) or control antibody (ctrl Ab) at weekly intervals at 20 mg/Kg two days after i.v. injection of T-ALL cells (5 × 106 cells/mouse) from 2 pediatric PDXs (A- PDTALL46, B- PDTALL39) and 1 adult PDXs (C- PDTALL-AD4). Antibodies injections are indicated by arrows. Top panels show leukemia engraftment by serial blood drawings and flow cytometric analysis of circulating blasts after first blood drawing, 7–19 days from the beginning of the experiment. The last blood drawing was obtained at sacrifice, when initial signs of illness appeared in control. Bottom panels display quantification of leukemia cells in the spleen and the BM at sacrifice. Statistically significant differences are indicated ** P < 0.01; *** P < 0.001 t-test. D: RNAseq analysis of OMP-52M51-acute treated PDTALL46 mice. Gene Set Enrichment Analysis (GSEA) plots and heat maps of the top 25 down-regulated differentially expressed genes in PDTALL46 anti-NOTCH1 OMP-52M51 (anti-N1) treated mice compared to mice treated with control antibody alone (3–4 samples/group). Red and blue indicate higher and lower expression levels, respectively. The columns represent individual samples. E-F: In vitro effect of OMP-52M51 (anti-N1) with antimetabolite drugs in T-ALL PDXs cells. Representation of IC50 values calculated for each chemotherapeutic drug alone or in combination with OMP-52M51 assessed by cleaved caspase-3/7 activity. IC50 values are expressed as the mean ± S.D. of at least three independent experiments. * P < 0.05. Values are reported in Additional file 1: Table S3. G: visualization of the therapeutic scheme to compare the in vivo efficacy of COMBO1 and COMBO2 drugs alone or in combination with anti-NOTCH1 antibody in PDTALL46 model