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

Casey D S Katerndahl, Lynn M. Heltemes-Harris, Mark J L Willette, Christine M. Henzler, Seth Frietze, Rendong Yang, Hilde Schjerven, Kevin A T Silverstein, Laura B. Ramsey, Gregory Hubbard, Andrew D. Wells, Roland P. Kuiper, Blanca Scheijen, Frank N. van Leeuwen, Markus Müschen, Steven M. Kornblau, Michael A. Farrar

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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-κ B1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κ 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-κ 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.

Original languageEnglish (US)
Pages (from-to)694-704
Number of pages11
JournalNature immunology
Issue number6
StatePublished - May 18 2017

Bibliographical note

Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.


Dive into the research topics of 'Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival'. Together they form a unique fingerprint.

Cite this