TY - JOUR
T1 - Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival
AU - Katerndahl, Casey D.S.
AU - Heltemes-Harris, Lynn M.
AU - Willette, Mark J.L.
AU - Henzler, Christine M.
AU - Frietze, Seth
AU - Yang, Rendong
AU - Schjerven, Hilde
AU - Silverstein, Kevin A.T.
AU - Ramsey, Laura B.
AU - Hubbard, Gregory
AU - Wells, Andrew D.
AU - Kuiper, Roland P.
AU - Scheijen, Blanca
AU - Van Leeuwen, Frank N.
AU - Müschen, Markus
AU - Kornblau, Steven M.
AU - Farrar, Michael A.
N1 - Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2017/5/18
Y1 - 2017/5/18
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85016928871
U2 - 10.1038/ni.3716
DO - 10.1038/ni.3716
M3 - Article
C2 - 28369050
AN - SCOPUS:85016928871
SN - 1529-2908
VL - 18
SP - 694
EP - 704
JO - Nature immunology
JF - Nature immunology
IS - 6
ER -