Fig. 4: DNA2 is essential for activated OXPHOS in MM cells.

A Oxygen consumption rates (OCRs) in JJN3 cells treated with NT or ILF2 ASOs (1 µM) for 3 weeks prior to receiving ASOs alone or in combination with 1 µM NSC for 72 h. Each data point is the mean ± S.D. of replicates (NT ASOs+Veh, n = 5; NT ASOs+NSC, n = 5; ILF2 ASOs+Veh, n = 4; ILF2 ASOs+NSC, n = 5). FCCP, carbonyl cyanide-p-trifluoromethoxy-phenylhydrazone; R/A, rotenone/antimycin; Veh, vehicle. Data are expressed as the mean ± S.D. from one representative experiment. Experiments were performed in biological duplicates. B ROS production in JJN3 cells treated with NT or ILF2 ASOs (1 μM) for 3 weeks prior to receiving 1 µM NSC for 48 h. Data are expressed as the mean ± S.D. from one representative experiment performed in triplicate. Statistically significant differences were detected using two-way ANOVA (****P < 0.0001; NT ASOs+Veh vs NT ASOs+NSC: P < 0.0001; NT ASOs+Veh vs ILF2 ASOs+Veh: P < 0.0001; NT ASOs+NSC vs ILF2 ASOs+NSC: P < 0.0001; ILF2 ASOs+Veh vs ILF2 ASOs+NSC: P < 0.0001). C Representative transmission electron micrographs showing the mitochondrial ultrastructure of JJN3 cells treated with NT or ILF2 ASOs (1 μM) for 3 weeks prior to receiving 1 µM NSC for 48 h. Scale bars: 7500X, 2000 nm (top); 20,000X, 800 nm (middle); 50,000X, 200 nm (bottom). D Numbers of live PCs isolated from the BM of MM patients with PI-based therapy failure (n = 7) after treatment with vehicle (Veh) or 2 µM NSC for 48 h over a layer of mesenchymal cells. Data were normalized to each sample’s vehicle (Veh)-treated control. Statistical significance was calculated using a paired 2-tailed Student t test (****P < 0.0001). E UMAP of scRNA-seq data displaying PCs from one MM patient (RD192) with 1q21 amplification, whose disease failed PI-based therapy. Cells were treated for 48 h with vehicle (Veh) or 2 µM NSC over a layer of mesenchymal cells. Different colors represent the sample origins. F Pathway enrichment analysis of genes that were significantly upregulated in all 3 NSC-treated MM PC samples shown in Fig. 4E, and Supplementary Fig. 4I, J compared with those treated with vehicle (Veh). The top 10 Hallmark gene sets are shown. Source data are provided as a Source Data file.