1. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma
- Author
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Adina Grunn, Francesco Bertoni, Marta Scandurra, Maurilio Ponzoni, Manisha Brahmachary, Laura Pasqualucci, Amy Chadburn, Subhadra V. Nandula, Govind Bhagat, Qiong Shen, Andrea Califano, Riccardo Dalla-Favera, Mara Compagno, Wei Keat Lim, Compagno, M, Lim, Wk, Grunn, A, Nandula, Sv, Brahmachary, M, Shen, Q, Bertoni, F, Ponzoni, Maurilio, Scandurra, M, Califano, A, Bhagat, G, Chadburn, A, Dalla Favera, R, and Pasqualucci, L.
- Subjects
Somatic cell ,Apoptosis ,Biology ,medicine.disease_cause ,MAP3K7 ,TNFAIP3 ,Article ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Humans ,Tumor Necrosis Factor alpha-Induced Protein 3 ,Regulation of gene expression ,Genetics ,Mutation ,Multidisciplinary ,Intracellular Signaling Peptides and Proteins ,NF-kappa B ,Nuclear Proteins ,Cell cycle ,medicine.disease ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Genes ,Cancer research ,Lymphoma, Large B-Cell, Diffuse ,Carcinogenesis ,Diffuse large B-cell lymphoma - Abstract
Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL(1). Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kappa B transcription complex(2). However, except for a small fraction of cases(3), it remains unclear whether NF-kappa B activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB- DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A ( RANK)) regulators of NF-kappa B. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-kappa B responses, is most commonly affected, with similar to 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kappa B. Thus, our results demonstrate that NF-kappa B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappa B responses.
- Published
- 2009