Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR−ABL tyrosine kinase
Paolo Vigneri1, 2, 3
& Jean Y. J. Wang1, 2
1
Department of Biology, University of California at San Diego, La Jolla, California, USA
2
Cancer Center, University of California at San Diego, La Jolla, California, USA
3
Universita' degli Studi di Catanzaro, Magna Graecia, Catanzaro, Italy
Correspondence should be addressed to Jean Y. J. Wang jywang@ucsd.edu
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.
