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

Nat Immunol. 2017 Jun;18(6):694-704. doi: 10.1038/ni.3716. Epub 2017 Apr 3.

Authors

Casey D S Katerndahl¹, Lynn M Heltemes-Harris¹, Mark J L Willette¹, Christine M Henzler², Seth Frietze³, Rendong Yang², Hilde Schjerven⁴, Kevin A T Silverstein², Laura B Ramsey⁵, Gregory Hubbard¹, Andrew D Wells⁶, Roland P Kuiper⁷, Blanca Scheijen^{8

9}, Frank N van Leeuwen⁸, Markus Müschen¹⁰, Steven M Kornblau¹¹, Michael A Farrar¹

Affiliations

¹ Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
² Supercomputing Institute for Advanced Computational Research, University of Minnesota, Minneapolis, Minnesota, USA.
³ MLRS Department, University of Vermont, Burlington, Vermont, USA.
⁴ Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
⁵ Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁷ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
⁸ Laboratory of Pediatric Oncology Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
⁹ Department of Pathology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
¹⁰ Department of Systems Biology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Pasadena, California, USA.
¹¹ Department of Leukemia, The University of Texas Maryland Anderson Cancer Center, Houston, Texas, USA.

PMID: 28369050
PMCID: PMC5540372
DOI: 10.1038/ni.3716

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.

MeSH terms

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*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma / mortality
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

Substances

Adaptor Proteins, Signal Transducing
B cell linker protein
Ebf1 protein, mouse
IKZF1 protein, human
Interferon Regulatory Factors
NF-kappa B p50 Subunit
PAX5 Transcription Factor
Pax5 protein, mouse
Pre-B Cell Receptors
Proto-Oncogene Proteins
STAT5 Transcription Factor
Trans-Activators
Zfpn1a1 protein, mouse
interferon regulatory factor-4
proto-oncogene protein Spi-1
Nfkb1 protein, mouse
Ikaros Transcription Factor
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human
Prkcb protein, mouse
Protein Kinase C beta

Abstract

MeSH terms

Substances

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