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 kappa B (NF kappa B) subunit c-REL (reticuloendotheliosis viral oncogene homolog) in a pilot series. Herein, we analyzed c-REL subcellular localization in additional primary MLBCLs and characterized NF kappa B 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 NF kappa B binding activity. MLBCL cells expressing a superrepressor form of inhibitor of kappa B alpha signaling (I kappa B alpha) had a markedly higher rate of apoptosis, implicating constitutive NF kappa B 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 NF kappa B target gene signatures of MLBCL and specific DLBCL subtypes. MLBCLs expressed increased levels of NF kappa B targets that promote cell survival and favor antiapoptotic tumor necrosis factor alpha (TNF alpha) signaling. In contrast, activated B cell (ABC)-like DLBCLs had a more restricted, potentially developmentally regulated, NF kappa B target gene signature. Of interest, the newly characterized host response DLBCL subtype had a robust NF kappa B target gene signature that partially overlapped that of primary MLBCL. In this large series of primary MLBCLs and DLBCLs, NF kappa B activation was not associated with amplification of the cREL locus, suggesting alternative pathogenetic mechanisms.