IκBε deficiency accelerates disease development in chronic lymphocytic leukemia

J Bordini, C Lenzi, M Frenquelli*, A Morabito, A Pseftogas, D Belloni, L Mansouri, G Tsiolas, E Perotta, P Ranghetti, F Gandini, F Genova, D Hägerstrand, G Gavriilidis, S Keisaris, N Pechlivanis, F Davi, NE Kay, AW Langerak, S PospisilovaL Scarfò, A Makris, FE Psomopoulos, K Stamatopoulos, R Rosenquist, A Campanella*, P Ghia

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1287-1298
Number of pages12
JournalLeukemia
Volume38
Issue number6
Early online date4 Apr 2024
DOIs
Publication statusE-pub ahead of print - 4 Apr 2024

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.

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