Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.
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.
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
Mara
M
Compagno
Wei Keat
WK
Lim
Adina
A
Grunn
Subhadra V
SV
Nandula
Manisha
M
Brahmachary
Qiong
Q
Shen
Francesco
F
Bertoni
Maurilio
M
Ponzoni
Marta
M
Scandurra
Andrea
A
Califano
Govind
G
Bhagat
Amy
A
Chadburn
Riccardo
R
Dalla-Favera
Laura
L
Pasqualucci
D017209:Apoptosis; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D005796:Genes / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3