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Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells.

Lyn kinase functions as a regulator of imatinib sensitivity in chronic myelogenous leukemia (CML) cells through an unknown mechanism. In patients who fail imatinib therapy but have no detectable BCR-ABL kinase mutation, we detected persistently activated Lyn kinase. In imatinib-resistant CML cells and patients, Lyn activation is BCR-ABL independent, it is complexed with the Gab2 and c-Cbl adapter/scaffold proteins, and it mediates persistent Gab2 and BCR-ABL tyrosine phosphorylation in the presence or absence of imatinib. Lyn silencing or inhibition is necessary to suppress Gab2 and BCR-ABL phosphorylation and to recover imatinib activity. Lyn also negatively regulates c-Cbl stability, whereas c-Cbl tyrosine phosphorylation is mediated by BCR-ABL. These results suggest that Lyn exists as a component of the BCR-ABL signaling complex and, in cells with high Lyn expression or activation, BCR-ABL kinase inhibition alone (imatinib) is not sufficient to fully disengage BCR-ABL-mediated signaling and suggests that BCR-ABL and Lyn kinase inhibition are needed to prevent or treat this form of imatinib resistance.

Pubmed ID: 18235045


  • Wu J
  • Meng F
  • Lu H
  • Kong L
  • Bornmann W
  • Peng Z
  • Talpaz M
  • Donato NJ



Publication Data

April 1, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: P01 CA 49639

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Benzamides
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Fusion Proteins, bcr-abl
  • Gene Silencing
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Multiprotein Complexes
  • Mutation
  • Phosphorylation
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-cbl
  • Pyrimidines
  • Signal Transduction
  • src-Family Kinases