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. 2024 Apr 10;38(6):1223–1235. doi: 10.1038/s41375-024-02241-7

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — A Sensitivity of primary (n = 4) and PDX (n = 13) leukemic cells exposed to increasing concentrations of NAV (0.1–1000 nM) for 96 h in ex vivo co-culture with hTERT-immortalized MSCs. Drug responses were determined by fluorescence image-based microscopy in at least technical duplicate and normalized to respective vehicle (DMSO) controls. IC₅₀ values are based on live cell enumeration. N = 1 independent experiment in at least duplicate. The gray boundary indicates the IC₅₀ range. B Heat map of most synergistic area Bliss synergy scores (S_area) for idasanutlin with navitoclax combination activity in primary (n = 4) and PDX (n = 10) ALL samples ex vivo. Leukemic samples included relapse patients and patients with subtypes linked to unfavorable survival. N = 1 independent experiments in at least duplicate. C Representative dose-response matrix analyses showing cell inhibition (top) and synergistic landscape (bottom) across diverse idasanutlin-navitoclax dose combinations. D Apoptotic cells were quantified by annexin-V flow cytometry in PDX samples (n = 3) following exposure to respective IC₅₀ concentrations of idasanutlin, navitoclax, or their combination for 48 h. Error bars show mean ± s.d. Combination treated cells were compared to respective single drugs by paired t-tests. E Apoptotic cells were quantified by annexin-V flow cytometry in PDX#4 cells following exposure to indicated concentrations of idasanutlin ± navitoclax (8 nM) for 24 h (n = 3). Error bars show mean ± s.d. Data were analyzed by two-way ANOVA with Tukey posttest for multiple comparisons. F Immunoblots showing induction of cleaved PARP (Asp214) in PDX samples (n = 3) following exposure to respective IC₅₀ concentrations of idasanutlin, navitoclax, or their combination for 24 h. ɑ-tubulin served as the loading control. ns=not significant, *p value < 0.05, ***p value < 0.001, ****p value < 0.0001.