The Unsolved Puzzle of c-Rel in B Cell Lymphoma

Abstract

Aberrant constitutive activation of Rel/NF-κB transcription factors is a hallmark of numerous cancers. Of the five Rel family members, c-Rel has the strongest direct links to tumorigenesis. c-Rel is the only member that can malignantly transform lymphoid cells in vitro. Furthermore, c-Rel is implicated in human B cell lymphoma through the frequent occurrence of REL gene locus gains and amplifications. In normal physiology, high c-Rel expression predominates in the hematopoietic lineage and a diverse range of stimuli can trigger enhanced expression and activation of c-Rel. Both expression and activation of c-Rel are tightly regulated on multiple levels, indicating the necessity to keep its functions under control. In this review we meta-analyze and integrate studies reporting gene locus aberrations to provide an overview on the frequency of REL gains in human B cell lymphoma subtypes, namely follicular lymphoma, diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, and classical Hodgkin lymphoma. We also summarize current knowledge on c-Rel expression and protein localization in these human B cell lymphomas and discuss the co-amplification of BCL11A with REL. In addition, we highlight and illustrate key pathways of c-Rel activation and regulation with a specific focus on B cell biology.

Keywords: B cells; DLBCL; FL; NF-κB; PMBCL; REL gene locus amplification; c-Rel; cHL; lymphoma.

Figure 1

Human c-Rel protein domains—schematic illustration. Amino acid start and end points of represented protein domains are indicated by numbers below the scheme. The position of the amino acid sequence encoded by exon 9 (aa 308–330) is highlighted by dotted lines. RHD, Rel homology domain; RID, Rel inhibitory domain; TAD, transactivation domain; NLS, nuclear localization signal. This figure is based on [9,15]. Other references assign the RHD to aa 8–290 [21] or aa 8–297 (UniProt database, UniProtKB, Q04864 REL (human), www.uniprot.org).

Figure 2

Activation of c-Rel signaling by the canonical NF-κB pathway in B cells. Major signaling and regulatory components described in the main text are illustrated. (1) Cardinal triggers of c-Rel signaling include B cell receptor (BCR), toll-like receptor (TLR) or CD40 stimulation. (2) In Btk-deficient B cells c-Rel DNA-binding activity is strongly reduced following stimulation. (3) The paracaspase mucosa-associated lymphoid tissue protein 1 (MALT1) which is part of the CBM complex is specifically required for BCR signal-induced c-Rel nuclear translocation. (4) In mature B cells the predominant NF-κB dimers are formed by c-Rel and p50. (5) c-Rel is sequestered in the cytoplasm by interaction with the inhibitory proteins IκBα, IκBβ and IκBε. Various upstream stimuli of canonical NF-κB signaling can target these IκB proteins for proteasomal degradation. (6) c-Rel is modified on a post-translational level. These post-translational modifications (M) can influence c-Rel transactivation and transforming activity. (7) Once released from the inhibitory IκB proteins, c-Rel translocates into the nucleus and binds to κB target sites to exert its function as a transcription factor. (8) PI3K signaling contributes to maintaining c-Rel levels in B cells. (9) Regulation of c-Rel is mediated by ubiquitination and subsequent proteasomal degradation. (10) REL mRNA levels are controlled on a post-transcriptional level. References as well as further details and abbreviations are provided in the main text. In addition to references cited in the main text, the content of this figure is based on Okkenhaug and Vanhaesebroeck, 2003 [65], Siebenlist et al. 2005 [66], and Murphy et al. 2007 [67]. P, phosphorylation; U, ubiquitination; M, post-translational modification.