We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma.
- Authors
Compagno, Mara; Lim, Wei Keat; Grunn, Adina; Nandula, Subhadra V.; Brahmachary, Manisha; Shen, Qiong; Bertoni, Francesco; Ponzoni, Maurilio; Scandurra, Marta; Califano, Andrea; Bhagat, Govind; Chadburn, Amy; Dalla-Favera, Riccardo; Pasqualucci, Laura
- 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-κB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-κB 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-κB. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-κB responses, is most commonly affected, with ∼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-κB. Thus, our results demonstrate that NF-κB 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-κB responses.
- Subjects
B cell lymphoma; GENE expression; GENETIC mutation; UBIQUITIN; TRANSCRIPTION factors; ENZYME activation; CELL lines; APOPTOSIS; GROWTH factors; TUMOR suppressor proteins
- Publication
Nature, 2009, Vol 459, Issue 7247, p717
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature07968