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

被引:258
作者
Vigneri, P
Wang, JYJ [1 ]
机构
[1] Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USA
[3] Univ Studi Catanzaro, Catanzaro, Italy
关键词
D O I
10.1038/84683
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:228 / 234
页数:7
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