A diphtheria toxin interleukin-3 fusion protein synergizes with tyrosine kinase inhibitors in killing leukemic progenitors from BCR/ABL positive acute leukemia

Despite initial remissions, most patients with Ph chromosome positive (Ph+) acute leukemia (AL) become refractory to tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib. This study was designed to determine if targeting the interleukin-3 receptor (IL-3R) with a diphtheria toxin fusion protein (DT388IL3) would improve the effectiveness of TKIs against Ph+ AL cells. IL-3R subunits were detected on most Ph+ cells and the IC50 for killing of colony forming cell (CFC) with DT388IL3 correlated with the level of IL-3Rα subunit by FACS. DT388IL3 synergized with both imatinib and dasatinib for killing of malignant CFCs. Long-term suspension culture-initiating cells (SC-ICs) and quiescent leukemic cells (G0 in cell cycle) also were studied and synergistic interactions were again demonstrated. Thus, cotreatment with TKIs and DT388IL3 is much more effective in eliminating Ph+ leukemic progenitors that express IL-3R than either agent alone.