Mutations of multiple genes cause deregulation of NF-kB in diffuse large B-cell lymphoma

By M. Compagno, W. Lim, A. Grunn, S. Nandula, M. Brahmachary, Qiong Shen, F. Bertoni, M. Ponzoni, M. Scandurra, Andrea Califano and 4 more. Nature, 2009

1,105 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/503ec345db3cf3250cbbcba17eea6478b8e3ff35

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Citations in the corpus

Toll-Like Receptor Signaling Pathways (2014, background): “A mutation in A20, which is a negative regulator of TLR signaling, is also associated with B-cell lymphoma development (82, 83).”
MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. (2013, background): “Mutations of multiple genes have recently been identified that encode proteins involved in the signaling of the B-cell receptor and members of the tumor necrosis factor receptor superfamily, as well as those involving NF-kB regulation.(2,3) Despite the identification of many deregulated target genes”
Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. (2011, background): “Collectively, these changes have been referred to as the senescence-associated secretory phenotype (SASP) or senescence messaging secretome (SMS) (Coppe et al. 2008; Kuilman and Peeper 2009).”
Somatic mutation of EZH2 (Y641) in Follicular and Diffuse Large B-cell Lymphomas of Germinal Center Origin (2010, background): “Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-κB pathwa”
Breaking the chains: structure and function of the deubiquitinases (2009, background): “A20 also acts as a tumour suppressor in human B cell lymphom”