Abstract
Piracy of the NF-κB transcription factors signaling pathway, to sustain its activity, is a mechanism often deployed in B-cell lymphoma to promote unlimited growth and survival. The aggressive activated B-cell like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) exploits a multi-protein complex of CARMA1, BCL10, and MALT1 (CBM complex), which normally conveys NF-κB signaling upon antigen receptors engagement. Once assembled, the CBM also unleashes MALT1 protease activity to finely tune the immune response. As a result, ABC DLBCL tumors develop a profound addiction to NF-κB and to MALT1 enzyme, leaving open a breach for therapeutics. However, the pleiotropic nature of NF-κB jeopardizes the success of its targeting and urges us to develop new strategies. In this review, we discuss how post-translational modifications, such as phosphorylation and ubiquitination of the CBM components, as well as, MALT1 proteolytic activity, shape the CBM activity in lymphocytes and ABC DLBCL, and may provide new avenues to restore vulnerability in lymphoma.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most prevalent aggressive B-cell non-Hodgkin lymphoma (NHL) and accounts for 30–40% of diagnosed NHL [1, 2]
This was resolved with the discovery of mutations in the immune receptor tyrosine-based activation motive of CD79A or CD79B in 20% of activated B-cell like (ABC) DLBCL, that lead to an effective hijacking of the downstream B-cell receptor (BCR) signaling [13]
L265P is the most common Myeloid differentiation primary response 88 (MYD88) mutation found in ABC DLBCL (29%), while it is rare in the germinal center B-cell like (GCB) subtype [21]
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most prevalent aggressive B-cell non-Hodgkin lymphoma (NHL) and accounts for 30–40% of diagnosed NHL [1, 2]. In ABC DLBCL, experiments with tandem ubiquitin-binding entities (TUBE) to selectively enrich for polyubiquitinated proteins showed that BCL10 is merely attached to K63-linked chains [75] This non-degradative ubiquitination requires an intact CBM complex and was proposed to recruit the LUBAC complex and allow IKK activation [15, 34, 36, 75, 76]. MALT1 K63-linked poly-ubiquitination has been observed in lymphocytes shortly following antigen receptor stimulation, as well as, in ABC DLBCL [14, 34, 44, 73, 79, 80] In their seminal work, Oeckinghaus et al identified 11 putative Lysine acceptors in the COOH-terminal segment of the protein, which abolished ubiquitination and recruitment of IKK when mutated to Arginines [14]. Because this DUB presents inactivating mutations in several hematological malignancies, studying the status and role of A20 processing
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
