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.

IκBε deficiency accelerates disease development in chronic lymphocytic leukemia / Bordini, J.; Lenzi, C.; Frenquelli, M.; Morabito, A.; Pseftogas, A.; Belloni, D.; Mansouri, L.; Tsiolas, G.; Perotta, E.; Ranghetti, P.; Gandini, F.; Genova, F.; Hagerstrand, D.; Gavriilidis, G.; Keisaris, S.; Pechlivanis, N.; Davi, F.; Kay, N. E.; Langerak, A. W.; Pospisilova, S.; Scarfo, L.; Makris, A.; Psomopoulos, F. E.; Stamatopoulos, K.; Rosenquist, R.; Campanella, A.; Ghia, P.. - In: LEUKEMIA. - ISSN 0887-6924. - (2024). [10.1038/s41375-024-02236-4]

IκBε deficiency accelerates disease development in chronic lymphocytic leukemia

Bordini J.
Co-primo
;
Morabito A.;Campanella A.
Penultimo
;
Ghia P.
Ultimo
2024-01-01

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.
File in questo prodotto:
File Dimensione Formato  
s41375-024-02236-4.pdf

solo gestori archivio

Tipologia: PDF editoriale (versione pubblicata dall'editore)
Licenza: Copyright dell'autore
Dimensione 4.92 MB
Formato Adobe PDF
4.92 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/159978
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact