Imatinib mesylate (IM, also termed Gleevec) has replaced interferon alpha (IFNa) as the standard of care for patients with newly diagnosed chronic myeloid leukemia (CML) due to higher response frequency, lesser toxicity and better survival. While rapidly killing differentiated CML cells, IM fails to act against more primitive leukemic stem cells and early progenitors. As a result, patients receiving IM are not cured and require life-long treatment that is often compromised by resistance to IM due to mutations in molecular target of IM - the Bcr-Abl tyrosine kinase. There are indications that in order to achieve curative effect in CML patients, a combination of inhibitors of Bcr-Abl and the leukemic stem cell-targeting agents (such as IFNa) might be required. While a few reports on success in patients receiving both types of therapy provide new enthusiasm for the re-introduction of IFNa into the management of CML, the molecular mechanisms that underlie the rationale for combining Bcr-Abl inhibitors with IFNa remain to be delineated. Our preliminary data demonstrates that Bcr-Abl activity stimulates the phosphorylation-mediated downregulation of IFNAR1 - a protein receptor that is central for all of the effects of IFNa on cells. This downregulation might confer a suppression of cellular responses to IFNa reported in CML cells. We propose a hypothesis that signal transduction pathways induced and sustained by Bcr-Abl impede the responses of CML cells to IFNa via inducing phosphorylation-dependent degradation of IFNAR1. We also hypothesize that accelerated degradation of IFNAR1 induced by Bcr-Abl plays an important role in regulating the sensitivity of CML cells to IM and IFNa. In this application, we propose to test this hypothesis by (i) determining the role of Bcr-Abl-induced downregulation of IFNAR1 in the inhibitory effect of Bcr-Abl on cellular responses of cells to IFNa;(ii) delineating the mechanisms by which BCR-Abl down-regulates IFNAR1 and its signaling;and (iii) assessing the role IFNAR1 stabilization plays in the therapeutic efficacy of IFNa and BCR-Abl inhibitors. We anticipate that these studies will provide significant insight into the mechanisms by which CML cells expressing constitutively active Bcr-Abl promote IFNAR1 degradation, suppress IFNa signaling and evade IFN-induced anti-tumor defenses. We also predict that these studies will identify critical regulators of these responses that can potentially serve as novel and important targets for increasing the efficacy of therapy against CML. Finally, the outlined experiments will provide the pre-clinical evaluation for sequence-specific combining of Bcr-Abl inhibitors with IFNa to optimize the existing regimes for CML management.

Public Health Relevance

Constitutive activity of Bcr-Abl fusion protein kinase causes chronic myeloid leukemia (CML). Inhibitors of Bcr-Abl such as imatinib have replaced the cytokine interferon alpha (IFNa) as the primary treatment for the management of patients with this malignancy. We found that Bcr-Abl signaling might impair cellular responses to IFNa by downregulating its receptor. Here we investigate the relationship between Bcr-Abl activity and IFNa signaling as well as the relationship between the molecular basis of the combination of imatinib and IFNa for CML treatment. These studies will yield results that are important for improving treatment of patients with CML.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-OTC-D (02))
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Veterinary Sciences
Schools of Veterinary Medicine
United States
Zip Code
Yu, Qiujing; Carbone, Christopher J; Katlinskaya, Yuliya V et al. (2015) Type I interferon controls propagation of long interspersed element-1. J Biol Chem 290:10191-9
Yu, Qiujing; Katlinskaya, Yuliya V; Carbone, Christopher J et al. (2015) DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function. Cell Rep 11:785-797
Bhattacharya, Sabyasachi; Katlinski, Kanstantsin V; Reichert, Maximilian et al. (2014) Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury. EMBO Mol Med 6:384-97
Sato, T; Tran, T H; Peck, A R et al. (2014) Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression. Oncogene 33:2215-24
Carbone, Christopher J; Fuchs, Serge Y (2014) Eliminative signaling by Janus kinases: role in the downregulation of associated receptors. J Cell Biochem 115:8-16
Fuchs, Serge Y (2013) Hope and fear for interferon: the receptor-centric outlook on the future of interferon therapy. J Interferon Cytokine Res 33:211-25
Zheng, Hui; Gupta, Vibhor; Patterson-Fortin, Jeffrey et al. (2013) A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell Rep 5:180-93
Bhattacharya, S; HuangFu, W-C; Dong, G et al. (2013) Anti-tumorigenic effects of Type 1 interferon are subdued by integrated stress responses. Oncogene 32:4214-21
Chitnis, Nilesh S; Pytel, Dariusz; Bobrovnikova-Marjon, Ekaterina et al. (2012) miR-211 is a prosurvival microRNA that regulates chop expression in a PERK-dependent manner. Mol Cell 48:353-64
Fuchs, Serge Y (2012) Ubiquitination-mediated regulation of interferon responses. Growth Factors 30:141-8

Showing the most recent 10 out of 21 publications