Combined treatment with SLC-391 (SLC) and venetoclax (VEN) inhibits mitochondrial OXPHOS in primitive AML cells. (A) Flow cytometry was used to quantify mitochondrial content using MitoTracker Deep Red (MTDR) in CD34⁺ cells from patients with AML (n = 2; patients #2 and #13) 72 hours posttreatment with the indicated drugs (left panels). Flow cytometry was used to quantify MitoRed mitochondrial superoxide indicator (MitoSOX) in CD34⁺ AML cells after 4 hours of treatment with the indicated drugs via flow cytometry (right panels). (B-D) OCR and the extracellular acidification rate (ECAR) were measured in MV4-11 cells (B), OCI-AML3 cells (C), and cells from patients with AML (D; patients #2, #3, and #6) after a 1-hour treatment with the indicated drugs. Maximal OCR and spare capacity were analyzed and compared among each treatment condition. Each point is representative of multiple replicates (B-C) or the mean of multiple replicates from each patient sample (D). The P values were calculated using 1-way ANOVA with Tukey’s post hoc correction for multiple comparisons or a 2-tailed, unpaired Student t test. (E) Model showing how inhibition of AXL activity sensitizes AML stem/progenitor cells to VEN in vitro and in PDX models, by dual targeting of AXL-mediated pathways and BCL-2.