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Regulation of the interferon regulatory factor-8 (IRF-8) tumor suppressor gene by the signal transducer and activator of transcription 5 (STAT5) transcription factor in chronic myeloid leukemia.
Waight, Jeremy D; Banik, Debarati; Griffiths, Elizabeth A; Nemeth, Michael J; Abrams, Scott I.
Afiliación
  • Waight JD; From the Departments of Immunology.
  • Banik D; From the Departments of Immunology.
  • Griffiths EA; Pharmacology and Therapeutics, and Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263.
  • Nemeth MJ; From the Departments of Immunology, Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263 Michael.Nemeth@RoswellPark.org.
  • Abrams SI; Pharmacology and Therapeutics, and Scott.Abrams@RoswellPark.org.
J Biol Chem ; 289(22): 15642-52, 2014 May 30.
Article en En | MEDLINE | ID: mdl-24753251
Tyrosine kinase inhibitors such as imatinib can effectively target the BCR-ABL oncoprotein in a majority of patients with chronic myeloid leukemia (CML). Unfortunately, some patients are resistant primarily to imatinib and others develop drug resistance, prompting interest in the discovery of new drug targets. Although much of this resistance can be explained by the presence of mutations within the tyrosine kinase domain of BCR-ABL, such mutations are not universally identified. Interferon regulatory factor-8 (IRF-8) is a transcription factor that is essential for myelopoiesis. Depressed IRF-8 levels are observed in a majority of CML patients and Irf-8(-/-) mice exhibit a CML-like disease. The underlying mechanisms of IRF-8 loss in CML are unknown. We hypothesized that BCR-ABL suppresses transcription of IRF-8 through STAT5, a proximal BCR-ABL target. Treatment of primary cells from newly diagnosed CML patients in chronic phase as well as BCR-ABL(+) cell lines with imatinib increased IRF-8 transcription. Furthermore, IRF-8 expression in cell line models was necessary for imatinib-induced antitumor responses. We have demonstrated that IRF-8 is a direct target of STAT5 and that silencing of STAT5 induced IRF-8 expression. Conversely, activating STAT5 suppressed IRF-8 transcription. Finally, we showed that STAT5 blockade using a recently discovered antagonist increased IRF-8 expression in patient samples. These data reveal a previously unrecognized BCR-ABL-STAT5-IRF-8 network, which widens the repertoire of potentially new anti-CML targets.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Leucemia Mielógena Crónica BCR-ABL Positiva / Proteínas Supresoras de Tumor / Factores Reguladores del Interferón / Factor de Transcripción STAT5 Tipo de estudio: Prognostic_studies Límite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Biol Chem Año: 2014 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Leucemia Mielógena Crónica BCR-ABL Positiva / Proteínas Supresoras de Tumor / Factores Reguladores del Interferón / Factor de Transcripción STAT5 Tipo de estudio: Prognostic_studies Límite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Biol Chem Año: 2014 Tipo del documento: Article