Lyn regulation in “normal” and Lyn-overexpressing CML cells. Lyn expression and activation are heterogeneous in CML cells and may be altered by imatinib therapy. In early stage or untreated (“normal”) CML, BCR-ABL is upstream of Lyn and other Src-family kinases. BCR-ABL–mediated Lyn (or related kinase) activation provides essential, possibly lineage-specific, support for BCR-ABL–mediated transformation.^54,55  In this setting, BCR-ABL inhibition (with imatinib) reduces Lyn kinase activation and loss of signaling through BCR-ABL– and Lyn-mediated phosphorylation. Lyn complexes with c-Cbl, inducing partial control of Lyn stability, but Lyn does not regulate c-Cbl phosphorylation. Imatinib exposure alters Lyn expression or induces changes in upstream control of its activation. Through overexpression, autoactivation, or association with other adaptor proteins, Lyn activation acquires full or partial BCR-ABL independence, resulting in loss of control of Lyn activation with imatinib alone. Unregulated Lyn alters BCR-ABL signaling complexes, associating with Gab2, inducing its tyrosine phosphorylation, and maintaining or directing Y177 phosphorylation of BCR-ABL. These changes suppress or delay kinase inhibition by imatinib. Lyn overexpression also destabilizes c-Cbl, resulting in a reduction in its protein level. Tyrosine phosphorylation of c-Cbl is mediated by BCR-ABL in both normal and stressed CML cells, allowing it to maintain scaffold or recruitment activity. Lyn may function in a feedback loop with c-Cbl to maintain ubiquitination of substrates, altering protein stability. Stabilization of key ubiquitin-targeted proteins in leukemic cells may independently contribute to BCR-ABL–mediated transformation.^56,57