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

Nature Medicine volume 7, pages 228–234 (2001)Cite this article

Abstract

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.

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Figure 1: Nuclear entrapment of BCR–ABL.
Figure 2: STI571 stimulates nuclear accumulation of BCR–Abl–NES.
Figure 4: Irreversible killing of BCR–ABL-transformed cells.
Figure 3: Nuclear accumulation of BCR–ABL induces apoptosis in K562 cells.
Figure 5: Preferential killing of mouse bone marrow cells expressing BCR–ABL.

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Acknowledgements

We thank B. Druker for providing STI571; M. Yoshida for his gift of LMB; G. Daley for the TonB cell line; R. Ren for the MSCV-BCR–ABL/p210-IRES-GFP construct; and J. Feramisco and B. Smith for their assistance with deconvolution microscopy. This work was supported by NIH grants CA 43054 and HL57900 to JYJW, and a fellowship from the Lopiccola Foundation to PV.

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Authors and Affiliations

  1. Department of Biology, University of California at San Diego, La Jolla, California, USA

    Paolo Vigneri & Jean Y. J. Wang

  2. Cancer Center, University of California at San Diego, La Jolla, California, USA

    Paolo Vigneri & Jean Y. J. Wang

  3. Universita' degli Studi di Catanzaro, Magna Graecia, Catanzaro, Italy

    Paolo Vigneri

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Correspondence to Jean Y. J. Wang.

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Vigneri, P., Wang, J. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR–ABL tyrosine kinase. Nat Med 7, 228–234 (2001). https://doi.org/10.1038/84683

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