NFκB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes

Primary mediastinal large B-cell lymphoma (MLBCL) shares important clinical and molecular features with classic Hodgkin lymphoma, including nuclear localization of the nuclear factor κB (NFκB) subunit c-REL (reticuloendotheliosis viral oncogene homolog) in a pilot series. Herein, we analyzed c-REL subcellular localization in additional primary MLBCLs and characterized NFκB activity and function in a MLBCL cell line. The new primary MLBCLs had prominent c-REL nuclear staining, and the MLBCL cell line exhibited high levels of NFκB binding activity. MLBCL cells expressing a superrepressor form of inhibitor of kappa B alpha signaling (IκBα) had a markedly higher rate of apoptosis, implicating constitutive NFκB activity in MLBCL cell survival. The transcriptional profiles of newly diagnosed primary MLBCLs and diffuse large B-cell lymphomas (DLBCLs) were then used to characterize the NFκB target gene signatures of MLBCL and specific DLBCL subtypes. MLBCLs expressed increased levels of NFκB targets that promote cell survival and favor antiapoptotic tumor necrosis factor α (TNFα) signaling. In contrast, activated B cell (ABC)-like DLBCLs had a more restricted, potentially developmentally regulated, NFκB target gene signature. Of interest, the newly characterized host response DLBCL subtype had a robust NFκB target gene signature that partially overlapped that of primary MLBCL. In this large series of primary MLBCLs and DLBCLs, NFκB activation was not associated with amplification of the cREL locus, suggesting alternative pathogenetic mechanisms.