Title | Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Compagno M, Lim WKeat, Grunn A, Nandula SV, Brahmachary M, Shen Q, Bertoni F, Ponzoni M, Scandurra M, Califano A, Bhagat G, Chadburn A, Dalla-Favera R, Pasqualucci L |
Journal | Nature |
Volume | 459 |
Issue | 7247 |
Pagination | 717-21 |
Date Published | 2009 Jun 04 |
ISSN | 1476-4687 |
Keywords | Apoptosis, Cell Line, Tumor, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Genes, Humans, Intracellular Signaling Peptides and Proteins, Lymphoma, Large B-Cell, Diffuse, Mutation, NF-kappa B, Nuclear Proteins, Tumor Necrosis Factor alpha-Induced Protein 3 |
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. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kappaB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-kappaB 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-kappaB. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-kappaB responses, is most commonly affected, with approximately 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-kappaB. Thus, our results demonstrate that NF-kappaB 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-kappaB responses. |
DOI | 10.1038/nature07968 |
Alternate Journal | Nature |
PubMed ID | 19412164 |
Grant List | U54CA121852 / CA / NCI NIH HHS / United States P01 CA92625-07 / CA / NCI NIH HHS / United States R01AI066116 / AI / NIAID NIH HHS / United States |
Related Faculty:
Amy Chadburn, M.D.