Persistent LYN Signaling in Imatinib-Resistant, BCR-ABL–Independent Chronic Myelogenous Leukemia

Resistance to imatinib is commonly associated with reactivation of BCR-ABL signaling. Many such patients harbor a mutation in BCR-ABL that confers resistance to imatinib. In other patients, the leukemia cells appear to express increased amounts of BCR-ABL kinase. Identification of a BCR-ABL mutation provides an explanation for onset of imatinib resistance and indicates a clear treatment strategy: second-line therapy with an ABL kinase inhibitor that is active against the particular BCR-ABL variant kinase. In the clinical setting, nilotinib and dasatinib are used for this purpose; additional inhibitors are under development. However, not all cases of resistance can be attributed to a BCR-ABL mutation or enhanced expression. The phenomenon of BCR-ABL–independent resistance is probably more frequent than generally appreciated and of considerable clinical importance. At a mechanistic level, BCR-ABL–independent resistance is poorly understood. Although these patients may progress via clonal evolution, thus far relatively few key molecular players have been convincingly implicated.