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

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22 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 (US)
Pages (from-to)694-704
Number of pages11
JournalNature immunology
Volume18
Issue number6
DOIs
StatePublished - May 18 2017

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    Katerndahl, C. D. S., Heltemes-Harris, L. M., Willette, M. J. L., Henzler, C. M., Frietze, S., Yang, R., Schjerven, H., Silverstein, K. A. T., Ramsey, L. B., Hubbard, G., Wells, A. D., Kuiper, R. P., Scheijen, B., van Leeuwen, F. N., Müschen, M., Kornblau, S. M., & Farrar, M. A. (2017). Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nature immunology, 18(6), 694-704. https://doi.org/10.1038/ni.3716