Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy.

Détails

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Etat: Public
Version: Final published version
Licence: CC BY-NC-SA 4.0
ID Serval
serval:BIB_48D4D91B5119
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy.
Périodique
The Journal of experimental medicine
Auteur(s)
Oricchio E., Ciriello G., Jiang M., Boice M.H., Schatz J.H., Heguy A., Viale A., de Stanchina E., Teruya-Feldstein J., Bouska A., McKeithan T., Sander C., Tam W., Seshan V.E., Chan W.C., Chaganti R.S., Wendel H.G.
ISSN
1540-9538 (Electronic)
ISSN-L
0022-1007
Statut éditorial
Publié
Date de publication
30/06/2014
Peer-reviewed
Oui
Volume
211
Numéro
7
Pages
1379-1391
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Loss of cell cycle controls is a hallmark of cancer and has a well-established role in aggressive B cell malignancies. However, the role of such lesions in indolent follicular lymphoma (FL) is unclear and individual lesions have been observed with low frequency. By analyzing genomic data from two large cohorts of indolent FLs, we identify a pattern of mutually exclusive (P = 0.003) genomic lesions that impair the retinoblastoma (RB) pathway in nearly 50% of FLs. These alterations include homozygous and heterozygous deletions of the p16/CDKN2a/b (7%) and RB1 (12%) loci, and more frequent gains of chromosome 12 that include CDK4 (29%). These aberrations are associated with high-risk disease by the FL prognostic index (FLIPI), and studies in a murine FL model confirm their pathogenic role in indolent FL. Increased CDK4 kinase activity toward RB1 is readily measured in tumor samples and indicates an opportunity for CDK4 inhibition. We find that dual CDK4 and BCL2 inhibitor treatment is safe and effective against available models of FL. In summary, frequent RB pathway lesions in indolent, high-risk FLs indicate an untapped therapeutic opportunity.
Mots-clé
Animals, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Cell Line, Tumor, Cyclin-Dependent Kinase 4/antagonists & inhibitors, Cyclin-Dependent Kinase 4/genetics, Cyclin-Dependent Kinase 4/metabolism, Cyclin-Dependent Kinase Inhibitor p15/genetics, Cyclin-Dependent Kinase Inhibitor p15/metabolism, Cyclin-Dependent Kinase Inhibitor p16/genetics, Cyclin-Dependent Kinase Inhibitor p16/metabolism, Humans, Lymphoma, Follicular/drug therapy, Lymphoma, Follicular/genetics, Lymphoma, Follicular/metabolism, Lymphoma, Follicular/pathology, Male, Mice, Neoplasms, Experimental/drug therapy, Neoplasms, Experimental/genetics, Neoplasms, Experimental/metabolism, Neoplasms, Experimental/pathology, Proto-Oncogene Proteins c-bcl-2/genetics, Proto-Oncogene Proteins c-bcl-2/metabolism, Retinoblastoma Protein/genetics, Retinoblastoma Protein/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
06/07/2018 11:02
Dernière modification de la notice
21/08/2019 6:09
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