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

Blood, 2005. 106(4): p.1392-1399.. Published: 2005.08.14

Friedrich Feuerhake, Jeffery L. Kutok, Stefano Monti, Wen Chen, Ann S. LaCasce, Giorgio Cattoretti, Paul Kurtin, Geraldine S. Pinkus, Laurence de Leval, Nancy L. Harris, Kerry J. Savage, Donna Neuberg, Thomas M. Habermann, Riccardo Dalla-Favera, Todd R. Golub, Jon C. Aster, Margaret A. Shipp

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Abstract

Primary mediastinal large B-cell lymphoma (MLBCL) shares important clinical and molecular features with classical Hodgkin lymphoma, including nuclear localization of the c-REL NFkB subunit in a pilot series. Herein, we analyzed c-REL subcellular localization in additional primary MLBCLs and characterized NFkB activity and function in a MLBCL cell line. The new primary MLBCLs had near-uniform c-REL nuclear staining and the MLBCL cell line exhibited high levels of NFkB binding activity. MLBCL cells expressing a super-repressor form of IkBk had a markedly higher rate of apoptosis, implicating constitutive NFkB activity in MLBCL cell survival. The transcriptional profiles of newly diagnosed primary MLBCLs and DLBCLs were then used to characterize the NFkB target gene signatures of MLBCL and specific DLBCL subtypes. MLBCLs expressed increased levels of NFkB targets that promote cell survival and favor anti-apoptotic TNFa signaling. In contrast, "ABC-like" DLBCLs had a more restricted, potentially developmentally regulated, NFkB target gene signature. Of interest, the newly characterized "Host Response" DLBCL subtype had a robust NFkB target gene signature which partially overlapped that of primary MLBCL. In this large series of primary MLBCLs and DLBCLs, NFkB activation was not associated with amplification of the c-REL locus, suggesting alternative pathogenetic mechanisms.

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Supplemental Data

Description Link/Filename
Manuscript FF_NFKB_manuscr_revised.pdf
Supplementary Information FF_NFKB_suppl_revised.pdf
ASH '04 slides ASH04_friedrich.pdf
Super-repressor expression data (RMA) super.rma.res.gz
Super-repressor expression data (MAS5) super.mas5.res.gz