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

doi:10.1038/ni.3716

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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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-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB 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-κB 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 language	English
Pages (from-to)	694-704
Number of pages	11
Journal	Nature immunology
Volume	18
Issue number	6
DOIs	https://doi.org/10.1038/ni.3716
Publication status	Published - Jun 2017

Keywords

Adaptor Proteins, Signal Transducing/genetics
Agammaglobulinaemia Tyrosine Kinase
Animals
B-Lymphocytes
Chromatin Immunoprecipitation
Flow Cytometry
Gene Expression Regulation, Neoplastic
Humans
Ikaros Transcription Factor/genetics
Interferon Regulatory Factors/genetics
Mice
Multiplex Polymerase Chain Reaction
NF-kappa B p50 Subunit/genetics
PAX5 Transcription Factor/genetics
Pre-B Cell Receptors/genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
Prognosis
Protein Kinase C beta/genetics
Protein-Tyrosine Kinases/genetics
Proto-Oncogene Proteins/genetics
Real-Time Polymerase Chain Reaction
STAT5 Transcription Factor/metabolism
Signal Transduction
Survival Rate
Trans-Activators/genetics

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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

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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-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB 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-κB 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.",

keywords = "Adaptor Proteins, Signal Transducing/genetics, Agammaglobulinaemia Tyrosine Kinase, Animals, B-Lymphocytes, Chromatin Immunoprecipitation, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Ikaros Transcription Factor/genetics, Interferon Regulatory Factors/genetics, Mice, Multiplex Polymerase Chain Reaction, NF-kappa B p50 Subunit/genetics, PAX5 Transcription Factor/genetics, Pre-B Cell Receptors/genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics, Prognosis, Protein Kinase C beta/genetics, Protein-Tyrosine Kinases/genetics, Proto-Oncogene Proteins/genetics, Real-Time Polymerase Chain Reaction, STAT5 Transcription Factor/metabolism, Signal Transduction, Survival Rate, Trans-Activators/genetics",

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 = jun,

doi = "10.1038/ni.3716",

language = "English",

volume = "18",

pages = "694--704",

journal = "Nature immunology",

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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

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 - 2017/6

Y1 - 2017/6

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-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB 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-κB 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-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB 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-κB 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.

KW - Adaptor Proteins, Signal Transducing/genetics

KW - Agammaglobulinaemia Tyrosine Kinase

KW - Animals

KW - B-Lymphocytes

KW - Chromatin Immunoprecipitation

KW - Flow Cytometry

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Ikaros Transcription Factor/genetics

KW - Interferon Regulatory Factors/genetics

KW - Mice

KW - Multiplex Polymerase Chain Reaction

KW - NF-kappa B p50 Subunit/genetics

KW - PAX5 Transcription Factor/genetics

KW - Pre-B Cell Receptors/genetics

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics

KW - Prognosis

KW - Protein Kinase C beta/genetics

KW - Protein-Tyrosine Kinases/genetics

KW - Proto-Oncogene Proteins/genetics

KW - Real-Time Polymerase Chain Reaction

KW - STAT5 Transcription Factor/metabolism

KW - Signal Transduction

KW - Survival Rate

KW - Trans-Activators/genetics

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U2 - 10.1038/ni.3716

DO - 10.1038/ni.3716

M3 - Article

C2 - 28369050

SN - 1529-2908

VL - 18

SP - 694

EP - 704

JO - Nature immunology

JF - Nature immunology

IS - 6

ER -

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

Abstract

Keywords

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