cancers-14-01489.pdf (1.37 MB)
Targeting the non-canonical NF-?B pathway in chronic lymphocytic leukemia and multiple myeloma
journal contribution
posted on 2023-06-10, 03:01 authored by Thomas Burley, Emma KennedyEmma Kennedy, Georgia Broad, Melanie Boyd, David Li, Timothy Woo, Christopher West, Eleni Ladikou, Iona Ashworth, Christopher Fegan, Rosalynd Johnston, Simon MitchellSimon Mitchell, Simon P Mackay, Andrea PepperAndrea Pepper, Christopher PepperChristopher PepperIn this study, we evaluated an NF-?B inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B-and T-lymphocytes. Basal NF-?B subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-?B subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-?B subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r2 = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-?B subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-?B signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation.
History
Publication status
- Published
File Version
- Published version
Journal
CancersISSN
2072-6694Publisher
MDPIExternal DOI
Issue
6Volume
14Page range
1-17Article number
a1489Department affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-04-01First Open Access (FOA) Date
2022-04-01First Compliant Deposit (FCD) Date
2022-03-31Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC