title: Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα 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 IFNα 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 IFNα. Furthermore, introduction of Bcr-abl into non-CML cells inhibits the cellular responses to IFNα. 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-α/β receptor 1 chain of the type I interferon receptor, leading to attenuation of IFNα signaling. We discuss the relationship between Bcr-abl activity and IFNα signaling as a molecular basis of the combination of inhibitors of Bcr-abl and IFNα for CML treatment.
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Christos
authors.initials: C
authors.lastname: Tzimas
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D001549:Benzamides; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D007155:Immunologic Factors / Q000494:pharmacology*; D016898:Interferon-alpha / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D000091283:Protein Kinase D2; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta; D015398:Signal Transduction
chemical_list: D001549:Benzamides; C507964:IFNAR1 protein, human; D007155:Immunologic Factors; D016898:Interferon-alpha; D010879:Piperazines; D000091283:Protein Kinase D2; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053633:Receptor, Interferon alpha-beta; D000068877:Imatinib Mesylate; D011494:Protein Kinases; D016044:Fusion Proteins, bcr-abl