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.
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Casey D S
authors.initials: CDS
authors.lastname: Katerndahl
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Heltemes-Harris
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Mark J L
authors.initials: MJL
authors.lastname: Willette
authors.affiliation: Supercomputing Institute for Advanced Computational Research, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Henzler
authors.affiliation: MLRS Department, University of Vermont, Burlington, Vermont, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Frietze
authors.affiliation: Supercomputing Institute for Advanced Computational Research, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Rendong
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors.forename: Hilde
authors.identifier: 0000-0001-9287-3375
authors.initials: H
authors.lastname: Schjerven
authors.affiliation: Supercomputing Institute for Advanced Computational Research, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kevin A T
authors.initials: KAT
authors.lastname: Silverstein
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Hubbard
authors.affiliation: 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.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Wells
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.affiliation: Laboratory of Pediatric Oncology Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.|Department of Pathology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Blanca
authors.initials: B
authors.lastname: Scheijen
authors.affiliation: Laboratory of Pediatric Oncology Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Frank N
authors.initials: FN
authors.lastname: van Leeuwen
authors.affiliation: Department of Systems Biology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Pasadena, California, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Department of Leukemia, The University of Texas Maryland Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Michael A
authors.identifier: 0000-0002-5569-0366
authors.initials: MA
authors.lastname: Farrar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000235:genetics; D051379:Mice; D060885:Multiplex Polymerase Chain Reaction; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D051757:PAX5 Transcription Factor / Q000235:genetics; D054420:Pre-B Cell Receptors / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D064546:Protein Kinase C beta / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D015534:Trans-Activators / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000077329:Agammaglobulinaemia Tyrosine Kinase; D051740:Ikaros Transcription Factor; D050835:Interferon Regulatory Factors; D052002:NF-kappa B p50 Subunit; D051757:PAX5 Transcription Factor; D054420:Pre-B Cell Receptors; D064546:Protein Kinase C beta; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4; C113939:B cell linker protein; C489921:Ebf1 protein, mouse; C497239:IKZF1 protein, human; C497282:Pax5 protein, mouse; C497238:Zfpn1a1 protein, mouse; C073701:Nfkb1 protein, mouse; C000625949:BTK protein, human; C579055:Prkcb protein, mouse