title: Suppression of interferon (IFN)-inducible genes and IFN-mediated functional responses in BCR-ABL-expressing cells.
abstract: The interferons (IFNs) are cytokines that play key roles in host defense against viral infections and immune surveillance against cancer. We report that BCR-ABL transformation of hematopoietic cells results in suppression of IFN-dependent responses, including transcription of IFN-inducible genes and generation of IFN-mediated antiviral effects. BCR-ABL transformation suppresses expression of several IFN-regulated genes containing IFN-sensitive response element (ISRE) or GAS elements in their promoters, including Isg15, Irf1, Irf9, and Ifit2 (interferon-induced protein with tetratricopeptide repeats 2). Suppression of transcription of ISRE-containing genes is also seen in cells expressing various BCR-ABL kinase domain mutants, including T315I, H396P, Y253F, and E255K, but not kinase-defective BCR-ABL. Such effects are associated with impaired IFN-dependent phosphorylation of Stat1 on Tyr(701) and Stat3 on Tyr(705) and defective binding of Stat complexes to ISRE or GAS elements. Beyond suppression of Stat activities, BCR-ABL inhibits IFN-inducible phosphorylation/activation of the p38 MAPK, suggesting a dual mechanism by which this abnormal fusion protein blocks IFN transcriptional responses. The inhibitory activities of BCR-ABL ultimately result in impaired IFNalpha-mediated protection against encephalomyocarditis virus infection and reversal of IFN-dependent growth suppression. Altogether, our data provide evidence for a novel mechanism by which BCR-ABL impairs host defenses and promotes malignant transformation, involving dual suppression of IFN-activated signaling pathways.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Lakeside Veterans Affairs Medical Center, Chicago, Illinois 60611, USA.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Katsoulidis
authors.forename: Antonella
authors.initials: A
authors.lastname: Sassano
authors.forename: Beata
authors.initials: B
authors.lastname: Majchrzak-Kita
authors.forename: Nathalie
authors.initials: N
authors.lastname: Carayol
authors.forename: Patrick
authors.initials: P
authors.lastname: Yoon
authors.forename: Alison
authors.initials: A
authors.lastname: Jordan
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D020218:Response Elements; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014443:Tyrosine / Q000737:chemistry
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014443:Tyrosine; D007372:Interferons; D016044:Fusion Proteins, bcr-abl