Extended Data Fig. 3: Venetoclax disrupts mitochondrially bound BCL2 and decreases mitochondrial activities without affecting mitochondrial protein expression levels. | Nature Cancer

Extended Data Fig. 3: Venetoclax disrupts mitochondrially bound BCL2 and decreases mitochondrial activities without affecting mitochondrial protein expression levels.

From: Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia

Extended Data Fig. 3: Venetoclax disrupts mitochondrially bound BCL2 and decreases mitochondrial activities without affecting mitochondrial protein expression levels.The alternative text for this image may have been generated using AI.

(a) Purified mitochondria from U937, MOLM14, KG1A immunoblotted with the indicated antibodies. The experiment was performed once for 3 different AML cell lines. (b) Spare respiratory capacity of MOLM14, U937, KG1A and OCIAML3. OCIAML3, CTL/VEN *P=0.0305, CTL/AraC P=0.0635, CTL/VEN+AraC *P=0.0248, AraC/VEN+AraC **P=0.0019; U937, CTL/VEN *P=0.0203, CTL/AraC *P=0.0309, CTL/VEN+AraC P=0.5490, AraC/VEN+AraC *P=0.0329; MOLM14, CTL/VEN **P=0.0052, CTL/AraC *P=0.0361, CTL/VEN+AraC P=0.1431, AraC/VEN+AraC *P=0.0125; KG1A, CTL/VEN *P=0.0169, CTL/AraC *P=0.0106, CTL/VEN+AraC ***P=0.0009, AraC/VEN+AraC **P=0.0027. (c,d) Western-Blotting for ETC complexes and HSP90 in cell lines (c) and primary AML samples (d). Two independent experiments were performed and a representative example is shown. (e,f) Mitochondrial mass using MTG probe in cell lines (e) and in PDXs (f). OCIAML3, CTL/AraC **P=0.0079, CTL/VEN+AraC P=0.6825, AraC/VEN+AraC P=0.8413; U937, CTL/AraC P=0.1270, CTL/VEN+AraC P=0.1270, AraC/VEN+AraC P=0.3095; MOLM14, CTL/AraC P=0.1270, CTL/VEN+AraC P=0.1270, AraC/VEN+AraC P=0.8413; KG1A, CTL/AraC P=0.6825, CTL/VEN+AraC **P=0.0079, AraC/VEN+AraC **P=0.0079; TUH07, D0/AraC P=0.0519, D0/VEN+AraC P=0.0823, AraC/VEN+AraC P=0.0931; TUH35, D0/AraC **P=0.0022, D0/VEN+AraC ***P=0.0007, AraC/VEN+AraC P=0.0926; TUH30, D0/AraC **P=0.0016, D0/VEN+AraC **P=0.0016, AraC/VEN+AraC P=0.2222. (g,h) Mitochondrial membrane potential using TMRE staining in 4 different cell lines (g) and in 3 different PDXs (h). OCIAML3, CTL/AraC **P=0.0079, CTL/VEN+AraC **P=0.0079, AraC/VEN+AraC *P=0.0159; U937, CTL/AraC **P=0.0079, CTL/VEN+AraC **P=0.0079, AraC/VEN+AraC P > 0.9999; MOLM14, CTL/AraC P=0.1270, CTL/VEN+AraC **P=0.0079, AraC/VEN+AraC P=0.1508; KG1A, CTL/AraC **P=0.0079, CTL/VEN+AraC **P=0.0079, AraC/VEN+AraC P=0.8413; TUH07, D0/AraC P=0.3853, D0/VEN+AraC P=0.7554, AraC/VEN+AraC P=0.6688; TUH35, D0/AraC **P=0.0087, D0/VEN+AraC ***P=0.0007, AraC/VEN+AraC P=0.0813; TUH30, D0/AraC **P=0.0031, D0/VEN+AraC **P=0.0016, AraC/VEN+AraC P=0.1508. (i) Mitochondrial calcium content using rhodamin2 probe. OCIAML3, CTL/AraC **P=0.0079, CTL/VEN+AraC **P=0.0079, AraC/VEN+AraC P=0.6905; U937, CTL/AraC **P=0.0079, CTL/VEN+AraC **P=0.0079, AraC/VEN+AraC P=0.5476; MOLM14, CTL/AraC **P=0.0079, CTL/VEN+AraC **P=0.0079, AraC/VEN+AraC P=0.8413; KG1A, CTL/AraC **P=0.0079, CTL/VEN+AraC **P=0.0079, AraC/VEN+AraC **P=0.0079. In B for OCIAML3 and KG1A n=3 independent experiments, for U937 and MOLM14 n=4 independent experiments. In E, G and I n=5 independent experiments. Mice number in F and H: TUH07, D0 n=5, AraC n=6, VEN+AraC n=6; for TUH35, D0 n=6, AraC n=5, VEN+AraC n=8; TUH30, D0 n=8, AraC n=5, VEN+AraC n=5. Data in B, E, F, G, H and I are displayed as mean ± s.e.m. Data analysis in B, E, F, G, H and I is by two-tailed unpaired Student’s t-test with Welch’s correction for unequal variance.

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