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.
Vigneri
P
P
Department of Biology, University of California at San Diego, La Jolla, California, USA.
Wang
J Y
JY
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D001549:Benzamides; D001854:Bone Marrow Cells / Q000166:cytology; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D001549:Benzamides; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C038753:leptomycin B