TRAF3 loss-of-function reveals the noncanonical NF-κB pathway as a therapeutic target in diffuse large B cell lymphoma.

Autor:	Li MY; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada.; Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC V6T 2B5, Canada., Chong LC; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Duns G; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Lytle A; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Woolcock B; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Jiang A; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada.; Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC V6T 2B5, Canada., Telenius A; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Ben-Neriah S; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Nawaz W; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Slack GW; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada.; Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC V6T 2B5, Canada., Elisia I; Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Viganò E; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Aoki T; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Healy S; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Krystal G; Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Venturutti L; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada.; Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC V6T 2B5, Canada.; Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada., Scott DW; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada.; Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC V6T 2B5, Canada., Steidl C; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada.; Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Apr 30; Vol. 121 (18), pp. e2320421121. Date of Electronic Publication: 2024 Apr 25.
DOI:	10.1073/pnas.2320421121
Abstrakt:	Here, we report recurrent focal deletions of the chr14q32.31-32 locus, including TRAF3 , a negative regulator of NF-κB signaling, in de novo diffuse large B cell lymphoma (DLBCL) (24/324 cases). Integrative analysis revealed an association between TRAF3 copy number loss with accumulation of NIK, the central noncanonical (NC) NF-κB kinase, and increased NC NF-κB pathway activity. Accordingly, TRAF3 genetic ablation in isogenic DLBCL model systems caused upregulation of NIK and enhanced NC NF-κB downstream signaling. Knockdown or pharmacological inhibition of NIK in TRAF3-deficient cells differentially impaired their proliferation and survival, suggesting an acquired onco-addiction to NC NF-κB. TRAF3 ablation also led to exacerbated secretion of the immunosuppressive cytokine IL-10. Coculturing of TRAF3-deficient DLBCL cells with CD8+ T cells impaired the induction of Granzyme B and interferon (IFN) γ, which were restored following neutralization of IL-10. Our findings corroborate a direct relationship between TRAF3 genetic alterations and NC NF-κB activation, and highlight NIK as a potential therapeutic target in a defined subset of DLBCL. Competing Interests: Competing interests statement:C.S. has performed consultancy for Bayer. D.W.S. has served as a consultant for Abbvie, AstraZenenca, Incyte, and Janssen. C.S. and D.W.S. are named inventors on a patent filed by the National Cancer Institute “Methods for determining lymphoma type.” The remaining authors declare no competing financial interests.
Databáze:	MEDLINE
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