Suppression of Interferon (IFN)-inducible Genes and IFN-mediated Functional Responses in BCR-ABL-expressing Cells

Efstratios Katsoulidis,Antonella Sassano,Beata Majchrzak-Kita,Nathalie Carayol,Patrick Yoon,Alison Jordan,Brian J Druker,Eleanor N Fish,Leonidas C Platanias

doi:10.1074/jbc.m706816200

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.

Highlights

To survive viral infection, cells produce and secrete interferons (IFNs),2 proinflammatory cytokines that inhibit cellular proliferation, block viral infection and replication, and exhibit important immunomodulatory activities
We examined whether BCR-ABL expression exerts regulatory effects on type I IFN-dependent, IFN-sensitive response element (ISRE)-driven, gene transcription
IFN␤ treatment led to a robust induction of ISRE-dependent transcription in cells transfected with the empty vector (Fig. 1B)

Summary

Introduction

Cells produce and secrete interferons (IFNs), proinflammatory cytokines that inhibit cellular proliferation, block viral infection and replication, and exhibit important immunomodulatory activities (reviewed in Refs. 1–7). The classical signaling pathways involve activation of Stat proteins, which form homo- and/or heterodimers, migrate to the nucleus, and bind to the promoters of IFN-regulated genes, leading to their induction or repression As mentioned above, IFNs activate the phosphatidylinositol 3Ј-kinase pathway and its effectors (9 –12, 21), a pathway well known to promote BCR-ABL-induced leukemogenesis [38] Such findings have raised the possibility that the type I IFN receptor and BCR-ABL compete for the utilization of certain common signaling elements and pathways that are required for the transmission of signals essential for generation of their biological effects. Overexpression of BCR-ABL in IFN-sensitive cells suppressed IFN␣-dependent transcriptional activity via ISRE elements in luciferase reporter assays and dramatically decreased the expression of several IFN-inducible genes known to mediate antiviral responses, such as Irf, Irf, Isg (interferon-stimulated gene 15), and Ifit. The generation of IFN␣-dependent antiviral and growth-inhibitory responses was suppressed in BCR-ABL-expressing Ba/F3 cells, indicating that the effects of BCR-ABL on IFN transcriptional activity translated to important antagonistic biological responses

Methods

Results

Conclusion