Abstract
The NFKBIE gene, which encodes the NF-κB inhibitor IκBε, is mutated in 3–7% of patients with chronic lymphocytic leukemia (CLL). The most recurrent alteration is a 4-bp frameshift deletion associated with NF-κB activation in leukemic B cells and poor clinical outcome. To study the functional consequences of NFKBIE gene inactivation, both in vitro and in vivo, we engineered CLL B cells and CLL-prone mice to stably down-regulate NFKBIE expression and investigated its role in controlling NF-κB activity and disease expansion. We found that IκBε loss leads to NF-κB pathway activation and promotes both migration and proliferation of CLL cells in a dose-dependent manner. Importantly, NFKBIE inactivation was sufficient to induce a more rapid expansion of the CLL clone in lymphoid organs and contributed to the development of an aggressive disease with a shortened survival in both xenografts and genetically modified mice. IκBε deficiency was associated with an alteration of the MAPK pathway, also confirmed by RNA-sequencing in NFKBIE-mutated patient samples, and resistance to the BTK inhibitor ibrutinib. In summary, our work underscores the multimodal relevance of the NF-κB pathway in CLL and paves the way to translate these findings into novel therapeutic options.
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Data availability
RNA-seq data may be found at the European Genome-Phenome Archive (EGA), https://ega-archive.org/ under accession number EGAS00001006771. For more details, contact corresponding authors.
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Acknowledgements
The research leading to these results has received funding from AIRC under IG 2017 - ID. 20246 – P.I. Ghia Paolo, IG 2022- ID. 27566, P.I. Ghia Paolo and under 5 per Mille 2018 - ID. 21198 program – P.I. Foà Roberto, G.L. Ghia Paolo. This research was also supported by the MH CR projects AZV No. NU20-08-00314 and FNBr 65269705 and National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Next Generation EU to SP.
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JB, CL, MF, AP, AC, PG designed the study. JB, CL, MF, AMo, DB, AMa and AP performed the experiments. GT prepared and provided the in vitro models. GG, SK, NP, FEP and FG performed the bioinformatic analysis. FD, NEK, AWL, SP and LS provided patient specimens. EP and PR performed sample purification and DNA/RNA extraction. FG, DH and LM performed NGS experiments. PG supervised most experiments and the overall implementation of the study and acquired funding. JB, CL, MF, AP, AC and PG interpreted data and wrote the manuscript. PG, RR and KS revised the manuscript. All authors analyzed data, reviewed and approved the final version of the manuscript.
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PG: honoraria/advisory board: AbbVie, Acerta/AstraZeneca, Adaptive, ArQule/MSD, BeiGene, CelGene/Juno, Gilead, Janssen, Loxo/Lilly, Sunesis; research funding: AbbVie, Gilead, Janssen, Novartis, Sunesis. RR: honoraria/advisory board: Abbvie, AstraZeneca, Janssen, Illumina and Roche. KS: honoraria/advisory board: AbbVie, Acerta/AstraZeneca, Gilead, Janssen; research funding: AbbVie, Gilead, Janssen.; NEK: Advisory Board for: AbbVie, Astra Zeneca, Beigene, Behring, Boehringer Ingelheim Pharmaceuticals, Inc., Dava Oncology, Janssen, Juno Therapeutics, Pharmacyclics. DSMC (Data Safety Monitoring Committee) for: Agios Pharm, AstraZeneca, BMS –Celgene, Dren Bio Janssen,. Research funding from: AbbVie, Acerta Pharma, Bristol Meyer Squib, Celgene, Genentech, Pharmacyclics, Sunesis, Vincerx.; LS: advisory board: AbbVie, AstraZeneca, Janssen.
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Bordini, J., Lenzi, C., Frenquelli, M. et al. IκBε deficiency accelerates disease development in chronic lymphocytic leukemia. Leukemia (2024). https://doi.org/10.1038/s41375-024-02236-4
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DOI: https://doi.org/10.1038/s41375-024-02236-4