A capture-sequencing strategy identifies IRF8, EBF1, and APRIL as novel IGH fusion partners in B-cell lymphoma

Blood. 2013 Aug 1;122(5):726-33. doi: 10.1182/blood-2013-04-495804. Epub 2013 Jun 17.


The characterization of immunoglobulin heavy chain (IGH) translocations provides information on the diagnosis and guides therapeutic decisions in mature B-cell malignancies while enhancing our understanding of normal and malignant B-cell biology. However, existing methodologies for the detection of IGH translocations are labor intensive, often require viable cells, and are biased toward known IGH fusions. To overcome these limitations, we developed a capture sequencing strategy for the identification of IGH rearrangements at nucleotide level resolution and tested its capabilities as a diagnostic and discovery tool in 78 primary diffuse large B-cell lymphomas (DLBCLs). We readily identified IGH-BCL2, IGH-BCL6, IGH-MYC, and IGH-CCND1 fusions and discovered IRF8, EBF1, and TNFSF13 (APRIL) as novel IGH partners in these tumors. IRF8 and TNFSF13 expression was significantly higher in lymphomas with IGH rearrangements targeting these loci. Modeling the deregulation of IRF8 and EBF1 in vitro defined a lymphomagenic profile characterized by up-regulation of AID and/or BCL6, down-regulation of PRMD1, and resistance to apoptosis. Using a capture sequencing strategy, we discovered the B-cell relevant genes IRF8, EBF1, and TNFSF13 as novel targets for IGH deregulation. This methodology is poised to change how IGH translocations are identified in clinical settings while remaining a powerful tool to uncover the pathogenesis of B-cell malignancies.

Publication types

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

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • Gene Library
  • Gene Rearrangement, B-Lymphocyte / genetics
  • HEK293 Cells
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Immunoglobulin Heavy Chains / genetics*
  • Interferon Regulatory Factors / genetics*
  • Interferon Regulatory Factors / physiology
  • Lymphoma, B-Cell / genetics*
  • Molecular Sequence Data
  • Oncogene Proteins, Fusion / genetics*
  • Trans-Activators / genetics*
  • Trans-Activators / physiology
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / genetics*
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / physiology
  • Validation Studies as Topic


  • EBF1 protein, human
  • Immunoglobulin Heavy Chains
  • Interferon Regulatory Factors
  • Oncogene Proteins, Fusion
  • TNFSF13 protein, human
  • Trans-Activators
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • interferon regulatory factor-8