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

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-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
Pages (from-to)694-704
Number of pages11
JournalNature Immunology
Volume18
Issue number6
DOIs
StatePublished - 18 May 2017
Externally publishedYes

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