期刊
NATURE IMMUNOLOGY
卷 18, 期 6, 页码 694-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3716
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资金
- US National Institutes of Health [R21CA209229, CA154998, CA151845, CA185062, R01CA137060, R01CA139032, R01CA157644, R01CA169458, R01CA172558, T32-AI07313, P50 PA100632]
- Cancer Research Institute
- Leukemia and Lymphoma Society
- Kindern Krankervrij [KIKA-55]
- University of Minnesota
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, PKC beta, NF-kappa B1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-kappa B 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-kappa B 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.
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