SM synergizes with HDACi across ALL PDXs in a RIPK1-dependent fashion. (A) Heat map depicting mean synergy scores (ZIP, Loewe, HSA, and Bliss) obtained from matrix synergy screens performed in 18 BCP-ALL and T-ALL, including relapse and diagnosis samples. White represents synergy scores <0; pink represents synergy scores between 0 and +5; red represents synergy scores above +5 (left). The Wilcoxon matched-pairs signed rank test revealing significant differences in mean ZIP scores between SM + Mo combination and the other combinations. Lighter dots, BCP-ALL; darker dots, T-ALL (right). (B) Individual sensitivities (log₁₀IC₅₀) toward SM or Mo and mean ZIP scores value for the SM + Mo combination, calculated for 47 BCP-ALL PDXs, grouped by subtype. (C) Immunoblot showing RIPK1 depletion after 6-hour treatment with LD4172 in 5 PDXs. GAPDH is used as a loading control. Dot plot depicting normalized logarithmic SM AUC (normalized AUC) upon SM treatment alone vs pretreatment with LD4172. (D) The Wilcoxon matched-pairs signed rank test indicating the significance of the variation in ZIP scores between SM + Mo combination with and without LD4172-mediated RIPK1 degradation, in 42 BCP-ALL PDXs. ns, P > .05; ∗∗∗P ≤ .001; ∗∗∗∗P ≤ .0001. Replicates within each PDX are indicated on respective underlying data table (supplemental Data 1). SM, birinapant. AUC, area under the curve; En, entinostat; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ns, not significant; Pa, panobinostat; UNT, untreated.