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 Druker, Eleanor N. Fish, Leonidas C. Platanias

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19 Citations (Scopus)

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 Tyr701 and Stat3 on Tyr705 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 IFNα-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.

Original languageEnglish (US)
Pages (from-to)10793-10803
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number16
DOIs
StatePublished - Apr 18 2008

Fingerprint

Interferons
Genes
Response Elements
Phosphorylation
Virus Diseases
Transcription
Phosphotransferases
Cells
Encephalomyocarditis virus
p38 Mitogen-Activated Protein Kinases
Viruses
Antiviral Agents
Proteins
Fusion reactions
Chemical activation
Cytokines

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Katsoulidis, E., Sassano, A., Majchrzak-Kita, B., Carayol, N., Yoon, P., Jordan, A., ... Platanias, L. C. (2008). Suppression of interferon (IFN)-inducible genes and IFN-mediated functional responses in BCR-ABL-expressing cells. Journal of Biological Chemistry, 283(16), 10793-10803. https://doi.org/10.1074/jbc.M706816200

Suppression of interferon (IFN)-inducible genes and IFN-mediated functional responses in BCR-ABL-expressing cells. / Katsoulidis, Efstratios; Sassano, Antonella; Majchrzak-Kita, Beata; Carayol, Nathalie; Yoon, Patrick; Jordan, Alison; Druker, Brian; Fish, Eleanor N.; Platanias, Leonidas C.

In: Journal of Biological Chemistry, Vol. 283, No. 16, 18.04.2008, p. 10793-10803.

Research output: Contribution to journalArticle

Katsoulidis, E, Sassano, A, Majchrzak-Kita, B, Carayol, N, Yoon, P, Jordan, A, Druker, B, Fish, EN & Platanias, LC 2008, 'Suppression of interferon (IFN)-inducible genes and IFN-mediated functional responses in BCR-ABL-expressing cells', Journal of Biological Chemistry, vol. 283, no. 16, pp. 10793-10803. https://doi.org/10.1074/jbc.M706816200
Katsoulidis, Efstratios ; Sassano, Antonella ; Majchrzak-Kita, Beata ; Carayol, Nathalie ; Yoon, Patrick ; Jordan, Alison ; Druker, Brian ; Fish, Eleanor N. ; Platanias, Leonidas C. / Suppression of interferon (IFN)-inducible genes and IFN-mediated functional responses in BCR-ABL-expressing cells. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 16. pp. 10793-10803.
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AU - Carayol, Nathalie

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