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

Abstract

Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal center 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-kB transcription complex2. However, except for a small fraction of cases3, it remains unclear whether NF-kB activation in these tumors represents an intrinsic program of the tumor 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/A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7/TAK1 and TNFRSF11A/RANK) regulators of NF-kB. Of these, the A20 gene, which encodes for a ubiquitin-modifying enzyme involved in termination of NF-kB 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 tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kB. Thus, our results demonstrate that NF-kB activation in DLBCL is caused by genetic lesions affecting multiple genes, whose loss or activation may promote lymphomagenesis by leading to abnormally prolonged NF-kB responses.

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…Bergsagel and colleagues reported a constitutive activation of NF-kB signaling in multiple myeloma as a result of mutations in the LTbR gene (Keats et al, 2007), emphasizing a critical role for the NF-kB pathway in its pathogenesis. Furthermore, constitutive NF-kB activity was detected in diffuse large B-cell lymphoma, indicating a role for this signaling pathway as a primary pathogenic event in lymphomagenesis (Compagno et al, 2009).…”

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

“…Moreover, most previous studies have evaluated only a subset of the NF-κB subunits. [8][9][10][11][12][13][14][15] There are only two studies using all five subunits in DLBCL-a cohort of 88 patients with DLBCL by Odqvist et al 16 and a cohort of 45 patients with testicular DLBCL by Menter et al 17 In the current study, we evaluated expression of all five subunits of the NF-κB protein by immunohistochemistry and its clinical implications in a large cohort of patients with de novo DLBCL.…”

Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

“…In addition to the crucial role of NF-kB in inflammation-associated tumourigenesis, recent studies point to a pivotal role of deregulated NF-kB activity in the pathogenesis of leukaemia and lymphoma (Compagno et al, 2009;Kato et al, 2009), as well as of solid tumours (Barbie et al, 2009;Kato et al, 2009;Meylan et al, 2009).…”