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

CDS Katerndahl, LM Heltemes-Harris, MJL Willette… - Nature …, 2017 - nature.com
CDS Katerndahl, LM Heltemes-Harris, MJL Willette, CM Henzler, S Frietze, R Yang
Nature immunology, 2017nature.com
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 …
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, 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.
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