title: A capture-sequencing strategy identifies IRF8, EBF1, and APRIL as novel IGH fusion partners in B-cell lymphoma.
abstract: 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.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Hakim
authors.initials: H
authors.lastname: Bouamar
authors.forename: Saman
authors.initials: S
authors.lastname: Abbas
authors.forename: An-Ping
authors.initials: AP
authors.lastname: Lin
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Daifeng
authors.initials: D
authors.lastname: Jiang
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Holder
authors.forename: Marsha C
authors.initials: MC
authors.lastname: Kinney
authors.forename: Scott
authors.initials: S
authors.lastname: Hunicke-Smith
authors.forename: Ricardo C T
authors.initials: RC
authors.lastname: Aguiar
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D015723:Gene Library; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics* / Q000502:physiology; D054928:Validation Studies as Topic; D000099185:Interferon Regulatory Factor-8
chemical_list: D007143:Immunoglobulin Heavy Chains; D050835:Interferon Regulatory Factors; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D000099185:Interferon Regulatory Factor-8; C081976:EBF1 protein, human; C114631:TNFSF13 protein, human