1. Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center,
2. Joint Centers for Systems Biology,
3. Department of Pathology & Cell Biology, Columbia University, New York, New York 10032, USA
4. Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland (IOSI), 6500 Bellinzona, Switzerland
5. Pathology Unit, Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, 20132 Milan, Italy
6. Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA
7. Department of Genetics & Development, Columbia University, New York, New York 10032, USA

Correspondence to: Laura Pasqualucci^1,3 Correspondence and requests for materials should be addressed to L.P. (Email: lp171@columbia.edu).

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) DLBCL¹. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-B transcription complex². However, except for a small fraction of cases³, it remains unclear whether NF-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-B. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-B 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-B. Thus, our results demonstrate that NF-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-B responses.

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