Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Blood. 2011 Oct 13;118(15):4179-87. doi: 10.1182/blood-2010-12-325373. Epub 2011 Aug 5.
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.
Bcr-abl 融合蛋白激酶的组成性活性导致慢性髓性白血病 (CML)。Bcr-abl 的抑制剂，如伊马替尼甲磺酸盐，已取代细胞因子 IFNα，成为治疗这种恶性肿瘤的主要方法。我们发现，伊马替尼甲磺酸盐预处理 CML 细胞可增强 IFNα 的抗增殖作用。此外，将 Bcr-abl 导入非 CML 细胞会抑制细胞对 IFNα 的反应。这种抑制是通过涉及蛋白激酶 D2 激活的机制介导的。后者促进干扰素-α/β受体 1 链的磷酸化依赖性降解，导致 IFNα 信号转导减弱。我们讨论了 Bcr-abl 活性与 IFNα 信号之间的关系，作为 Bcr-abl 抑制剂和 IFNα 联合用于 CML 治疗的分子基础。
