Publication Date:
2009-05-05
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973325/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973325/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- P01 CA092625/CA/NCI NIH HHS/ -- P01 CA092625-020003/CA/NCI NIH HHS/ -- P01 CA92625-07/CA/NCI NIH HHS/ -- R01 AI066116/AI/NIAID NIH HHS/ -- R01 AI066116-05/AI/NIAID NIH HHS/ -- R01AI066116/AI/NIAID NIH HHS/ -- U54 CA121852/CA/NCI NIH HHS/ -- U54 CA121852-05/CA/NCI NIH HHS/ -- U54CA121852/CA/NCI NIH HHS/ -- England -- Nature. 2009 Jun 4;459(7247):717-21. doi: 10.1038/nature07968. Epub 2009 May 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19412164" target="_blank"〉PubMed〈/a〉
Keywords:
Apoptosis
;
Cell Line, Tumor
;
DNA-Binding Proteins
;
*Gene Expression Regulation, Neoplastic
;
Genes/*genetics
;
Humans
;
Intracellular Signaling Peptides and Proteins/genetics
;
Lymphoma, Large B-Cell, Diffuse/*genetics/*physiopathology
;
Mutation/*genetics
;
NF-kappa B/antagonists & inhibitors/genetics/*metabolism
;
Nuclear Proteins/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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