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

Nat Med. 2001 Feb;7(2):228-34. doi: 10.1038/84683.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Apoptosis*
  • Benzamides
  • Bone Marrow Cells / cytology
  • Cell Line, Transformed
  • Cell Nucleus / metabolism*
  • Cytoplasm / metabolism
  • Enzyme Inhibitors / pharmacology
  • Fatty Acids, Unsaturated / pharmacology
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Mice
  • Piperazines / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrimidines / pharmacology
  • Tumor Cells, Cultured


  • Benzamides
  • Enzyme Inhibitors
  • Fatty Acids, Unsaturated
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • leptomycin B