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Published on: October 30, 2016
NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse
Friedrich Feuerhake1, Jeffery L Kutok, Stefano Monti
1Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
Insights
Nuclear factor kappaB (NFkappaB) pathway activation promotes survival in primary mediastinal large B-cell lymphoma (MLBCL). This pathway is crucial for MLBCL, but not driven by cREL gene amplification.
Area of Science:
- Molecular Biology
- Oncology
- Immunology
Background:
- Primary mediastinal large B-cell lymphoma (MLBCL) shares features with classic Hodgkin lymphoma.
- Nuclear factor kappaB (NFkappaB) pathway, specifically c-REL, is implicated in MLBCL pathogenesis.
Purpose of the Study:
- To analyze c-REL subcellular localization in primary MLBCL.
- To characterize NFkappaB activity and function in MLBCL cell lines.
- To compare NFkappaB target gene signatures between MLBCL and diffuse large B-cell lymphoma (DLBCL) subtypes.
Main Methods:
- Analysis of c-REL nuclear staining in primary MLBCL samples.
- Assessment of NFkappaB binding activity and apoptosis in an MLBCL cell line.
- Transcriptional profiling of MLBCL and DLBCL subtypes to identify NFkappaB target genes.
Main Results:
- Prominent nuclear c-REL staining observed in primary MLBCL.
- Constitutive NFkappaB activity promotes MLBCL cell survival.
- MLBCL exhibits increased NFkappaB targets supporting cell survival and TNFalpha signaling.
- Distinct NFkappaB target gene signatures identified in MLBCL, ABC-DLBCL, and host response DLBCL subtypes.
- NFkappaB activation in MLBCL and DLBCL is not linked to cREL gene amplification.
Conclusions:
- Constitutive NFkappaB pathway activation is a key survival mechanism in MLBCL.
- NFkappaB signaling in MLBCL is distinct from other DLBCL subtypes.
- Alternative mechanisms, not cREL amplification, drive NFkappaB activation in MLBCL.
Abstract:
Primary mediastinal large B-cell lymphoma (MLBCL) shares important clinical and molecular features with classic Hodgkin lymphoma, including nuclear localization of the nuclear factor kappaB (NFkappaB) subunit c-REL (reticuloendotheliosis viral oncogene homolog) in a pilot series. Herein, we analyzed c-REL subcellular localization in additional primary MLBCLs and characterized NFkappaB 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 NFkappaB binding activity. MLBCL cells expressing a superrepressor form of inhibitor of kappa B alpha signaling (IkappaB alpha) had a markedly higher rate of apoptosis, implicating constitutive NFkappaB 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 NFkappaB target gene signatures of MLBCL and specific DLBCL subtypes. MLBCLs expressed increased levels of NFkappaB targets that promote cell survival and favor antiapoptotic tumor necrosis factor alpha (TNFalpha) signaling. In contrast, activated B cell (ABC)-like DLBCLs had a more restricted, potentially developmentally regulated, NFkappaB target gene signature. Of interest, the newly characterized host response DLBCL subtype had a robust NFkappaB target gene signature that partially overlapped that of primary MLBCL. In this large series of primary MLBCLs and DLBCLs, NFkappaB activation was not associated with amplification of the cREL locus, suggesting alternative pathogenetic mechanisms.
