What is the role of NF kappa-B signaling in the molecular biology of DLBCL?

Updated: Jun 12, 2019
  • Author: Shipra Gandhi, MBBS; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Lymphoid malignancies usually avoid cell death by constitutive activation of the NFkB pathway. It is a transcription factor regulating the expression of the immunoglobulin kappa light chain. [57] In B cells, NFkB activation occurs transiently downstream of numerous receptors, including the BCR, CD40, the B-cell–activating factor (BAFF) receptor, and various Toll-like receptors (TLRs). [58] Alternatively, activation of NFkB results from the proteasome degradation of its inhibitor (inhibitor of kappa B [IkB]).

The hallmark of ABC-DLBCL is the activation of NFkB through the classic pathway. Many of the NFkB target genes are expressed in ABC-DLBCL compared with GCB-DLBCL, and this explains how genetic inhibition of this pathway is lethal to ABC- but not GCB-DLBCL lines. [59] Clinically, it has been observed that ABC-DLBCL patients are more refractory to standard immunochemotherapy than other DLBCL subtypes. This could be explained by the ability of NFkB to antagonize the antitumor activity of chemotherapy agents. [60] Moreover, pharmacological inhibitors of NFkB activity (ie, lenalidomide or bortezomib) appear to have selective activity in non–GCB-DLBCL. [45, 46]

Recently, additional mechanisms leading to an increase in NFkB activity have been described in ABC-DLBCL, particularly caspase recruitment domain 11 (CARD11) mutations. The survival of most ABC-DLBCL cell lines depends on the CBM complex (a signaling hub consisting of CARD11, BCL-10, and MALT1). [61] The CBM complex is required for activation of the classic NFkB pathway downstream of the antigen receptors in B and T cells. [62] CARD11 is a multidomain signaling adapter that contains (1) an amino-terminal CARD and coiled-coil domains, (2) an intervening linker domain, and (3) a C-terminal membrane-associated guanylate kinase (MAGUK) domain.

In normal resting conditions, CARD11 is located in the cytosol, where it is presumably kept in an inactive conformation through an intramolecular interaction between its coiled-coil and linker domains. Following signaling via the BCR, protein kinase C (PKC) beta–dependent serine phosphorylation within the CARD11 linker domain occurs and activates CRD11. [63] CARD11 is then able to translocate into the plasma membrane, where it binds to BCL10 and MALT1, forming the CBM complex. Subsequently, the CBM complex plays a pivotal role in the phosphorylation and proteasome degradation of IkB. CARD11 mutations resulting in constitutive engagement of the CBM complex have been described in 10% of ABC-DLBCL patients. [64]


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