IκBε deficiency accelerates disease development in chronic lymphocytic leukemia.

Autor: Bordini J; IRCSS Ospedale San Raffaele, Milan, Italy., Lenzi C; IRCSS Ospedale San Raffaele, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Frenquelli M; IRCSS Ospedale San Raffaele, Milan, Italy. frenquelli.michela@hsr.it., Morabito A; IRCSS Ospedale San Raffaele, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Pseftogas A; IRCSS Ospedale San Raffaele, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Belloni D; IRCSS Ospedale San Raffaele, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Mansouri L; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Tsiolas G; Centre for Research & Technology, Hellas (CERTH), Thessaloniki, Greece., Perotta E; IRCSS Ospedale San Raffaele, Milan, Italy., Ranghetti P; IRCSS Ospedale San Raffaele, Milan, Italy., Gandini F; IRCSS Ospedale San Raffaele, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Genova F; IRCSS Ospedale San Raffaele, Milan, Italy., Hägerstrand D; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden., Gavriilidis G; Centre for Research & Technology, Hellas (CERTH), Thessaloniki, Greece., Keisaris S; Centre for Research & Technology, Hellas (CERTH), Thessaloniki, Greece., Pechlivanis N; Centre for Research & Technology, Hellas (CERTH), Thessaloniki, Greece., Davi F; Institution Université Pierre et Marie Curie & Hôpital Pitié-Salpêtrière, Paris, France., Kay NE; Mayo Clinic, Rochester, USA., Langerak AW; Erasmus MC, Rottherdam, Netherlands., Pospisilova S; University Hospital Brno, Brno, Czech Republic.; Masaryk University, Brno, Czech Republic., Scarfò L; IRCSS Ospedale San Raffaele, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Makris A; Centre for Research & Technology, Hellas (CERTH), Thessaloniki, Greece., Psomopoulos FE; Centre for Research & Technology, Hellas (CERTH), Thessaloniki, Greece., Stamatopoulos K; Centre for Research & Technology, Hellas (CERTH), Thessaloniki, Greece., Rosenquist R; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden., Campanella A; IRCSS Ospedale San Raffaele, Milan, Italy. campanella.alessandro@hsr.it.; Vita-Salute San Raffaele University, Milan, Italy. campanella.alessandro@hsr.it., Ghia P; IRCSS Ospedale San Raffaele, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2024 Jun; Vol. 38 (6), pp. 1287-1298. Date of Electronic Publication: 2024 Apr 04.
DOI: 10.1038/s41375-024-02236-4
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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