Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival.
Nat Immunol
; 18(6): 694-704, 2017 06.
Article
em En
| MEDLINE
| ID: mdl-28369050
ABSTRACT
The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCß, NF-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4 and IKAROS. Patients with a high ratio of active STAT5 to NF-κB or IKAROS had more-aggressive disease. Our studies indicate that an imbalance of two opposing transcriptional programs drives B-ALL and suggest that restoring the balance of these pathways might inhibit B-ALL.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
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Regulação Neoplásica da Expressão Gênica
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Proteínas Adaptadoras de Transdução de Sinal
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Fator de Transcrição STAT5
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Fator de Transcrição Ikaros
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Receptores de Células Precursoras de Linfócitos B
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article