Exploiting mitochondrial vulnerability in therapies. (A) Illustration of Ven mechanism of action. (B-C) IC₅₀ curves (B) and quantification of apoptotic cells (C) of OCI-AML2 control (sgCtr) and TRMT5 KO (sg2, sg4) cells in the presence of Ven (n = 3 biological replicates averaged over 3 technical replicates). (D) Western blot revealing protein levels of endogenously degron- and HA-tagged TRMT5 (HA) after treatment with dTAG-V1 at the indicated concentrations (top panels) or 24 and 48 hours after treatment with 500 nM dTAG-V1 (bottom panels). WO indicates washout and sample harvested after 24 hours. VCL served as loading control. (E) Illustration of combinatorial treatment of TRMT5 degron-tagged OCI-AML2 with Ven and dTAG-V1 at the indicated days (d). (F) Bliss score calculation of synergistic effect of Ven and dTAG-V1 treatment on cell death (Annexin V) at the indicated concentration. (G) Illustration of combinatorial treatment of Ven, AraC, and dTAG-V1 at the indicated days (d). (H) Synergistic effect of dTAG, Ven, and AraC on cell viability (nonlinear curve fitting). Illustrated are 2 independent OCI-AML2 tagged clones. Mean ± SD (panels B-C). Dunnett multiple comparison test (panel C). IC₅₀, 50% inhibitory concentration.