Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR–ABL tyrosine kinase

The chimeric BCR–ABL oncoprotein is the molecular hallmark of chronic myelogenous leukemia (CML). BCR–ABL contains nuclear import and export signals but it is localized only in the cytoplasm where it activates mitogenic and anti-apoptotic pathways. We have found that inhibition of the BCR–ABL tyrosine kinase, either by mutation or by the drug STI571, can stimulate its nuclear entry. By combining STI571 with leptomycin B (LMB) to block nuclear export, we trapped BCR–ABL in the nucleus and the nuclear BCR–ABL tyrosine kinase activates apoptosis. As a result, the combined treatment with STI571 and LMB causes the irreversible and complete killing of BCR–ABL transformed cells, whereas the effect of either drug alone is fully reversible. The combined treatment with STI571 and LMB also preferentially eliminates mouse bone marrow cells that express BCR–ABL. These results indicate that nuclear entrapment of BCR–ABL can be used as a therapeutic strategy to selectively kill chronic myelogenous leukemia cells.