Neutralization of B-Cell Activating Factor (BAFF) by Belimumab Reinforces Small Molecule Inhibitor Treatment in Chronic Lymphocytic Leukemia.

Détails

Ressource 1Télécharger: 204. Tandler et al.pdf (1706.21 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_200C5A22FFCC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Neutralization of B-Cell Activating Factor (BAFF) by Belimumab Reinforces Small Molecule Inhibitor Treatment in Chronic Lymphocytic Leukemia.
Périodique
Cancers
Auteur(s)
Tandler C., Schmidt M., Heitmann J.S., Hierold J., Schmidt J., Schneider P., Dörfel D., Walz J., Salih H.R.
ISSN
2072-6694 (Print)
ISSN-L
2072-6694
Statut éditorial
Publié
Date de publication
23/09/2020
Peer-reviewed
Oui
Volume
12
Numéro
10
Pages
E2725
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
The introduction of idelalisib, ibrutinib and venetoclax for treatment of chronic lymphocytic leukemia (CLL) has greatly improved long term survival of patients. However, many patients do not achieve complete remission and suffer from development of resistance upon treatment with these small molecule inhibitors. Here we report that the TNF family member B-cell activating factor (BAFF) mediates resistance of CLL cells to idelalisib, ibrutinib and venetoclax by sustaining survival and preventing apoptosis of the malignant B cells as revealed by analysis of cellular ATP levels and mitochondrial membrane integrity as well as caspase activation, respectively. As BAFF also plays a prominent role in autoimmune diseases, the BAFF-neutralizing antibody belimumab was developed and approved for treatment of systemic lupus erythematosus (SLE). When we employed belimumab in the context of CLL treatment with idelalisib, ibrutinib and venetoclax, BAFF neutralization was found to significantly increase the sensitivity of the leukemic cells to all three small molecule inhibitors. Notably, BAFF neutralization proved to be beneficial independently of clinical stage according to Binet and Rai or IgVH mutational status. Our results identify drug repurposing of belimumab for neutralization of BAFF to complement small molecule inhibitor treatment as a promising therapeutic approach in CLL that is presently undergoing clinical evaluation.
Mots-clé
B-cell activating factor, BAFF, belimumab, chronic lymphocytic leukemia, ibrutinib, idelalisib, venetoclax
Pubmed
Web of science
Open Access
Oui
Création de la notice
05/10/2020 14:55
Dernière modification de la notice
18/12/2020 8:08
Données d'usage