IκBε deficiency accelerates disease development in chronic lymphocytic leukemia

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Authors

BORDINI Jessica LENZI Chiara FRENQUELLI Michela MORABITO Alessia PSEFTOGAS Athanasios BELLONI Daniela MANSOURI Larry TSIOLAS George PEROTTA Eleonora RANGHETTI Pamela GANDINI Francesca GENOVA Francesca HAGERSTRAND Daniel GAVRIILIDIS Georgios KEISARIS Sofoklis PECHLIVANIS Nikolaos DAVI Frederic KAY Neil E LANGERAK Anton W POSPÍŠILOVÁ Šárka SCARFO Lydia MAKRIS Antonios PSOMOPOULOS Fotis E STAMATOPOULOS Kostas ROSENQUIST Richard CAMPANELLA Alessandro GHIA Paolo

Year of publication 2024
Type Article in Periodical
Magazine / Source Leukemia
MU Faculty or unit

Faculty of Medicine

Citation
Web https://www.nature.com/articles/s41375-024-02236-4
Doi http://dx.doi.org/10.1038/s41375-024-02236-4
Keywords chronic lymphocytic leukemia; I?B? deficiency
Description The NFKBIE gene, which encodes the NF-kappa B inhibitor I kappa B epsilon, 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-kappa B 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-kappa B activity and disease expansion. We found that I kappa B epsilon loss leads to NF-kappa B 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. I kappa B epsilon 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-kappa B pathway in CLL and paves the way to translate these findings into novel therapeutic options.
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