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Expression and Activity of the NF-κB Subunits in Chronic Lymphocytic Leukaemia: A Role for RelB and Non-Canonical Signalling

Lookup NU author(s): Dr Evan Mulligan, Dr Susan Tudhope, Dr Jill Hunter, Sarah Elliott, Dr Jonathan Wallis, Dr Stephany Veuger, Dr Elaine WillmoreORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2023 by the authors. Background: Canonical NF-κB signalling by p65 (RelA) confers chemo-resistance and poor survival in chronic lymphocytic leukaemia (CLL). The role of non-canonical NF-κB signalling (leading to RelB and p52 subunit activation) in CLL is less understood, but given its importance in other B-cell tumour types, we theorised that RelB and p52 may also contribute to the pathology of CLL. Methods: DNA binding activity of all five NF-kB subunits, p65, p50, RelB, p52, and c-Rel, was quantified using ELISA and correlated to ex vivo chemoresistance, CD40L-stimulated signalling (to mimic the lymph node microenvironment), and clinical data. Results: Importantly, we show for the first time that high basal levels of RelB DNA binding correlate with nuclear RelB protein expression and are associated with del(11q), ATM dysfunction, unmutated IGHV genes, and shorter survival. High levels of nuclear p65 are prevalent in del(17p) cases (including treatment-naïve patients) and also correlate with the outcome. CD40L-stimulation resulted in rapid RelB activation, phosphorylation and processing of p100, and subsequent CLL cell proliferation. Conclusions: These data highlight a role for RelB in driving CLL cell tumour growth in a subset of patients and therefore strategies designed to inhibit non-canonical NF-κB signalling represent a novel approach that will have therapeutic benefit in CLL.

Publication metadata

Author(s): Mulligan EA, Tudhope SJ, Hunter JE, Clift AEG, Elliott SL, Summerfield GP, Wallis J, Pepper CJ, Durkacz B, Veuger S, Willmore E

Publication type: Article

Publication status: Published

Journal: Cancers

Year: 2023

Volume: 15

Issue: 19

Online publication date: 26/09/2023

Acceptance date: 22/09/2023

Date deposited: 03/11/2023

ISSN (electronic): 2072-6694

Publisher: MDPI

URL: https://doi.org/10.3390/cancers15194736

DOI: 10.3390/cancers15194736

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