Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia.
Animals
Autoimmunity
/ immunology
B-Lymphocytes
/ immunology
Cell Line, Tumor
Cell Survival
/ immunology
Female
HEK293 Cells
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
/ immunology
Mice
Mice, Inbred C57BL
Mice, Transgenic
NF-kappa B
/ metabolism
Receptor Activator of Nuclear Factor-kappa B
/ metabolism
Signal Transduction
/ immunology
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 02 2021
01 02 2021
Historique:
received:
18
03
2020
revised:
30
07
2020
accepted:
03
09
2020
entrez:
19
10
2020
pubmed:
20
10
2020
medline:
10
9
2021
Statut:
ppublish
Résumé
Clinical evidence suggests alterations in receptor activator of NF-κB (RANK) signaling are key contributors to B cell autoimmunity and malignancy, but the pathophysiological consequences of aberrant B cell-intrinsic RANK signaling remain unknown. We generated mice that express a human lymphoma-derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK signaling disrupted B cell tolerance and induced a fully penetrant systemic lupus erythematosus-like disease in addition to the development of chronic lymphocytic leukemia (CLL). Importantly, RANKK240E transgenic CLL cells as well as CLL cells of independent murine and of human origin depend on microenvironmental RANK ligand (RANKL) for tumor cell survival. Consequently, inhibition of the RANKL-RANK axis with anti-RANKL antibodies killed murine and human CLL cells in vitro and in vivo. These results establish pathological B cell-intrinsic RANK signaling as a potential driver of autoimmunity and B cell malignancy, and they suggest the exploitation of clinically available anti-RANKL compounds for CLL treatment.
Identifiants
pubmed: 33075129
pii: 211464
doi: 10.1084/jem.20200517
pmc: PMC7868734
pii:
doi:
Substances chimiques
NF-kappa B
0
Receptor Activator of Nuclear Factor-kappa B
0
TNFRSF11A protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2020 Alankus et al.
Déclaration de conflit d'intérêts
Disclosures: W. Weichert reported personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Amgen, and Astellas, and grants from Roche, MSD, BMS, AZ, and Bruker outside the submitted work. No other disclosures were reported.
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