부산대학교 도서관

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 IGHtranslocations are labor intensive, often require viable cells, and are biased toward known IGHfusions. To overcome these limitations, we developed a capture sequencing strategy for the identification of IGHrearrangements 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-CCND1fusions and discovered IRF8, EBF1,and TNFSF13(APRIL) as novel IGHpartners in these tumors. IRF8and TNFSF13expression was significantly higher in lymphomas with IGHrearrangements 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 TNFSF13as novel targets for IGH deregulation. This methodology is poised to change how IGHtranslocations are identified in clinical settings while remaining a powerful tool to uncover the pathogenesis of B-cell malignancies.