Activation of native ABL1 enhances the efficacy of TKIs against leukemias expressing oncogenic ABL1 kinase mutants. (A) Phoenix cells overexpressing ABL1 were treated with dimethylsulfoxide (DMSO) (control), DPH, imatinib (IM), and a combination of imatinib followed by DPH (IM+DPH). (i) Representative western blot analysis of phospho-tyrosine 245-ABL1 (pY245-ABL1), ABL1, lamin-B and β-tubulin in nuclear (left panel) and cytoplasmic (right panel) cell lysates. Quantification of normalized pY245-ABL1 (ii) and ABL1 (iii) levels to lamin-B and β-tubulin. Bars represent mean percentage volume intensity ± SD. (B-G) Percentage of viable cells or colonies ± SD from cells treated for 72 hours with diluent (Control), imatinib (IM), ponatinib, DPH, and combinations: (B) BCR-ABL1 Abl1^−/− and BCR-ABL1 Abl1^+/+ cells, (C) Lin⁻CD34⁺ cells from 6 CML-CP patients and 3 healthy donors, (D) xenograft cells from 3 freshly diagnosed BCR-ABL1 B-ALL patients, (E) xenograft cells from 3 relapsed B-ALL patients carrying BCR-ABL1(T315I) mutation, (F) Baf3 and Baf3-TEL-ABL1 cells, (G) NUP214-ABL1–positive murine cells; *P < .001, **P < .05 as determined by the unpaired Student t test.