Transcription profiling of human frozen tumor biopsies from diffuse large cell lynohoma patients reveals mutations of multiple genes deregulate the NF-kB pathway 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) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kB transcription complex. However, except for a small fraction of cases, 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 at 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 the most commonly affected one, with ~30% of the patients displaying biallelic inactivation by mutations and/or deletions, suggesting 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. We show that most ABC-DLBCL and a smaller fraction of GCB-DLBCL display genetic lesions affecting multiple NFkB pathway genes, with A20 representing the most frequently mutated gene Experiment Overall Design: DLBCL biopsies from 73 patients were collected from the archives of the Departments of Pathology at Columbia University and Weill Cornell Medical College. Total RNA was extracted from frozen tumor biopsies and processed according to Affymetrix standard protocols. Purified tonsillar geminal center cells (centroblasts and centrocytes, 5 samples each from different individuals) were purified by magnetic cell separation as described in Klein et al, PNAS 2003.

ORGANISM(S): Homo sapiens

SUBMITTER: Laura Pasqualucci 

PROVIDER: E-GEOD-12195 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress