Fig. 9: SUMOylation blockade synergizes with HMAs in MDS and AML.

A ZIP synergy scores (with 95% CI) for combinatorial drug testing in MDS-L and AML lines determined by SynergyFinder. n = 88 drug combinations for MDS-L, Kasumi-1 and TF-1. n = 64 (AZA) or n = 66 (DAC) drug combinations for MOLM-13. The experiment was performed once. B, C Survival of polyclonally gene-edited MDS-L cells in 96-well plates in response to (B) AZA ± 0.1 µM TAK-981 or (C) DAC ± 0.1 µM TAK-981 added daily on days 1–4. TagRFP⁺ cells were counted on day 5 and normalized to vehicle counts (±SD), with n = 3 technical replicate cultures per data point. EC50 values are listed in Table S3. The experiment was performed once. D Mean fluorescence intensity ±SD of anti-γH2AX staining by FACS of fixed/permeabilized polyclonally gene-edited MDS-L cells drug-treated as in B, C; n = 3 biological replicates per group. Adjusted P values are from Tukey’s one-way ANOVA; only comparisons ±TAK-981 are shown. The experiment was performed once. E Mean cell cycle distributions ±SD for the same cultures as D (n = 3 biological replicates per treatment); Adjusted P values for fraction in G1 are from Tukey’s one-way ANOVA; only comparisons ±TAK-981 shown. F Event-free survival of non-irradiated MISTRG engrafted i.v. with MOLM-13 cells. Mice were sex and IVIS flux rank randomized in cohorts of 4 into treatment groups on day 10 (n = 7 mice for vehicle, AZA and AZA + TAK-981 groups; n = 6 mice for TAK-981 group), then drug treatments (20 mg/kg TAK-981 i.p., 0.6 mg/kg AZA s.c.) commenced on day 11. P values (one degree of freedom) from Gehan-Breslow-Wilcoxon tests; P > 0.05 comparisons not shown. G, H Expansion of AML PDX (top), and survival of drug-treated MISTRG PDX hosts (bottom). G Non-irradiated MISTRG mice were injected with 4 × 10⁶ AML-16 PDX cells i.v., or (H) sub-lethally irradiated MISTRG mice were injected with 1.25 × 10⁶ AML-5 PDX cells i.v. PDX-injected mice were then bled at approximately weekly intervals. The mice were randomized in sex and weight ranked cohorts of 4 into treatment groups on day 10 or 11 (AML-16: n = 6 mice per treatment group. AML-5: n = 6 mice for vehicle and AZA + TAK-981 groups; n = 5 mice for AZA and TAK-981 groups), then treated with drugs (20 mg/kg TAK-981 i.p., 0.6 mg/kg AZA s.c.) starting day 11 or 12. Event-free survival was time to reach 25% engraftment of huCD45⁺CD33⁺ cells in peripheral blood⁵⁸ (as indicated by broken y-axes in the spaghetti plots). P values (one degree of freedom) from Gehan-Breslow-Wilcoxon tests; P > 0.05 comparisons not shown. Source data are provided as a Source Data file.