Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival.

Citation data:

Nature immunology, ISSN: 1529-2916, Vol: 18, Issue: 6, Page: 694-704

Publication Year:
2017
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PMID:
28369050
DOI:
10.1038/ni.3716; 10.3410/f.727471210.793533456
Author(s):
Katerndahl, Casey D S; Heltemes-Harris, Lynn M; Willette, Mark J L; Henzler, Christine M; Frietze, Seth; Yang, Rendong; Schjerven, Hilde; Silverstein, Kevin A T; Ramsey, Laura B; Hubbard, Gregory; Wells, Andrew D; Kuiper, Roland P; Scheijen, Blanca; van Leeuwen, Frank N; Müschen, Markus; Kornblau, Steven M; Farrar, Michael A Show More Hide
Publisher(s):
Springer Nature; Faculty of 1000, Ltd.
Tags:
Immunology and Microbiology
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article description
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, PKCβ, 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.