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Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2.
Liu, Suhu; Walker, Sarah R; Nelson, Erik A; Cerulli, Robert; Xiang, Michael; Toniolo, Patricia A; Qi, Jun; Stone, Richard M; Wadleigh, Martha; Bradner, James E; Frank, David A.
Afiliação
  • Liu S; Authors' Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, and Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and Department of Immunology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil.
Mol Cancer Ther ; 13(5): 1194-205, 2014 May.
Article em En | MEDLINE | ID: mdl-24435449
The transcription factor signal STAT5 is constitutively activated in a wide range of leukemias and lymphomas, and drives the expression of genes necessary for proliferation, survival, and self-renewal. Thus, targeting STAT5 is an appealing therapeutic strategy for hematologic malignancies. Given the importance of bromodomain-containing proteins in transcriptional regulation, we considered the hypothesis that a pharmacologic bromodomain inhibitor could inhibit STAT5-dependent gene expression. We found that the small-molecule bromodomain and extra-terminal (BET) bromodomain inhibitor JQ1 decreases STAT5-dependent (but not STAT3-dependent) transcription of both heterologous reporter genes and endogenous STAT5 target genes. JQ1 reduces STAT5 function in leukemia and lymphoma cells with constitutive STAT5 activation, or inducibly activated by cytokine stimulation. Among the BET bromodomain subfamily of proteins, it seems that BRD2 is the critical mediator for STAT5 activity. In experimental models of acute T-cell lymphoblastic leukemias, where activated STAT5 contributes to leukemia cell survival, Brd2 knockdown or JQ1 treatment shows strong synergy with tyrosine kinase inhibitors (TKI) in inducing apoptosis in leukemia cells. In contrast, mononuclear cells isolated form umbilical cord blood, which is enriched in normal hematopoietic precursor cells, were unaffected by these combinations. These findings indicate a unique functional association between BRD2 and STAT5, and suggest that combinations of JQ1 and TKIs may be an important rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Serina-Treonina Quinases / Neoplasias Hematológicas / Inibidores de Proteínas Quinases / Fator de Transcrição STAT5 Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Mol Cancer Ther Assunto da revista: ANTINEOPLASICOS Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Serina-Treonina Quinases / Neoplasias Hematológicas / Inibidores de Proteínas Quinases / Fator de Transcrição STAT5 Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Mol Cancer Ther Assunto da revista: ANTINEOPLASICOS Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos