title: 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.
abstract: 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.
authors.affiliation: From the Departments of Immunology.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Waight
authors.affiliation: From the Departments of Immunology.
authors.forename: Debarati
authors.initials: D
authors.lastname: Banik
authors.affiliation: Pharmacology and Therapeutics, and Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Griffiths
authors.affiliation: From the Departments of Immunology, Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263 Michael.Nemeth@RoswellPark.org.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Nemeth
authors.affiliation: Pharmacology and Therapeutics, and Scott.Abrams@RoswellPark.org.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000068877:Imatinib Mesylate; D050835:Interferon Regulatory Factors; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D025521:Tumor Suppressor Proteins; D000099185:Interferon Regulatory Factor-8; C494092:STAT5A protein, human; C494095:STAT5B protein, human
keywords: Cancer Therapy; Cell Death; Leukemia; STAT Transcription Factor; Tumor Suppressor Gene
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