Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Constitutive activity of Bcr-abl fusion protein kinase causes chronic myeloid leukemia (CML). Inhibitors of Bcr-abl such as imatinib mesylate have replaced the cytokine IFN alpha as the primary treatment for the management of patients with this malignancy. We found that pretreatment of CML cells with imatinib mesylate augments the antigrowth effects of IFN alpha. Furthermore, introduction of Bcr-abl into non-CML cells inhibits the cellular responses to IFN alpha. This inhibition is mediated via a mechanism that involves activation of protein kinase D2. The latter promotes an accelerated phosphorylation-dependent degradation of the interferon-alpha beta receptor 1 chain of the type I interferon receptor, leading to attenuation of IFN alpha signaling. We discuss the relationship between Bcr-abl activity and IFN alpha signaling as a molecular basis of the combination of inhibitors of Bcr-abl and IFN alpha for CML treatment. (Blood. 2011;118(15):4179-4187)