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.