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 journalArticlepeer-review

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 languageEnglish
Pages (from-to)694-704
Number of pages11
JournalNature immunology
Volume18
Issue number6
DOIs
Publication statusPublished - 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

Fingerprint

Dive into the research topics of 'Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival'. Together they form a unique fingerprint.

Cite this