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

ABSTRACT: 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? 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?. Furthermore, introduction of Bcr-abl into non-CML cells inhibits the cellular responses to IFN?. 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-?/? receptor 1 chain of the type I interferon receptor, leading to attenuation of IFN? signaling. We discuss the relationship between Bcr-abl activity and IFN? signaling as a molecular basis of the combination of inhibitors of Bcr-abl and IFN? for CML treatment.

SUBMITTER: Bhattacharya S 

PROVIDER: S-EPMC3204736 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature