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 journalArticle

14 Citations (Scopus)

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

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
B-Lymphocytes
STAT5 Transcription Factor
Survival
PAX5 Transcription Factor
B-Cell Antigen Receptors
B-Lymphoid Precursor Cells
Genes

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

Cite this

Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. / Katerndahl, Casey D S; Heltemes-Harris, Lynn M.; Willette, Mark J L; Henzler, Christine M.; Frietze, Seth; Yang, Rendong; Schjerven, Hilde; Silverstein, Kevin A T; Ramsey, Laura B.; Hubbard, Gregory; Wells, Andrew D.; Kuiper, Roland P.; Scheijen, Blanca; van Leeuwen, Frank N.; Müschen, Markus; Kornblau, Steven M.; Farrar, Michael A.

In: Nature Immunology, Vol. 18, No. 6, 18.05.2017, p. 694-704.

Research output: Contribution to journalArticle

Katerndahl, CDS, Heltemes-Harris, LM, Willette, MJL, Henzler, CM, Frietze, S, Yang, R, Schjerven, H, Silverstein, KAT, Ramsey, LB, Hubbard, G, Wells, AD, Kuiper, RP, Scheijen, B, van Leeuwen, FN, Müschen, M, Kornblau, SM & Farrar, MA 2017, 'Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival', Nature Immunology, vol. 18, no. 6, pp. 694-704. https://doi.org/10.1038/ni.3716
Katerndahl, Casey D S ; Heltemes-Harris, Lynn M. ; Willette, Mark J L ; Henzler, Christine M. ; Frietze, Seth ; Yang, Rendong ; Schjerven, Hilde ; Silverstein, Kevin A T ; Ramsey, Laura B. ; Hubbard, Gregory ; Wells, Andrew D. ; Kuiper, Roland P. ; Scheijen, Blanca ; van Leeuwen, Frank N. ; Müschen, Markus ; Kornblau, Steven M. ; Farrar, Michael A. / Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. In: Nature Immunology. 2017 ; Vol. 18, No. 6. pp. 694-704.
@article{45e8ba595db648e29c31e5002813395f,
title = "Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival",
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.",
author = "Katerndahl, {Casey D S} and Heltemes-Harris, {Lynn M.} and Willette, {Mark J L} and Henzler, {Christine M.} and Seth Frietze and Rendong Yang and Hilde Schjerven and Silverstein, {Kevin A T} and Ramsey, {Laura B.} and Gregory Hubbard and Wells, {Andrew D.} and Kuiper, {Roland P.} and Blanca Scheijen and {van Leeuwen}, {Frank N.} and Markus M{\"u}schen and Kornblau, {Steven M.} and Farrar, {Michael A.}",
year = "2017",
month = "5",
day = "18",
doi = "10.1038/ni.3716",
language = "English (US)",
volume = "18",
pages = "694--704",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "6",

}

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.

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 - http://www.scopus.com/inward/record.url?scp=85016928871&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016928871&partnerID=8YFLogxK

U2 - 10.1038/ni.3716

DO - 10.1038/ni.3716

M3 - Article

C2 - 28369050

AN - SCOPUS:85016928871

VL - 18

SP - 694

EP - 704

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 6

ER -