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Pharmacological and genomic profiling identifies NF-{kappa}B-targeted treatment strategies for mantle cell lymphoma

Official URL:https://doi.org/10.1038/nm.3435
PubMed:View item in PubMed
Creators Name:Rahal, R. and Frick, M. and Romero, R. and Korn, J.M. and Kridel, R. and Chun Chan, F. and Meissner, B. and Bhang, H.E. and Ruddy, D. and Kauffmann, A. and Farsidjani, A. and Derti, A. and Rakiec, D. and Naylor, T. and Pfister, E. and Kovats, S. and Kim, S. and Dietze, K. and Doerken, B. and Steidl, C. and Tzankov, A. and Hummel, M. and Monahan, J. and Morrissey, M.P. and Fritsch, C. and Sellers, W.R. and Cooke, V.G. and Gascoyne, R.D. and Lenz, G. and Stegmeier, F.
Journal Title:Nature Medicine
Journal Abbreviation:Nat Med
Volume:20
Number:1
Page Range:87-92
Date:January 2014
Keywords:Base Sequence, Western Blotting, CARD Signaling Adaptor Proteins, Cell Line, Cell Survival, DNA Primers, Guanylate Cyclase, Inhibitor of Apoptosis Proteins, Luminescent Measurements, Mantle-Cell Lymphoma, Microarray Analysis, Molecular Sequence Data, NF-kappa B, Protein-Serine-Threonine Kinases, Pyrazoles, Pyrimidines, Pyrroles, Quinazolines, RNA Interference, Real-Time Polymerase Chain Reaction, B-Cell Antigen Receptors, RNA Sequence Analysis, Signal Transduction, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 3, Trypan Blue
Abstract:Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis. Large-scale pharmacological profiling across more than 100 hematological cell line models identified a subset of MCL cell lines that are highly sensitive to the B cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin. Sensitive MCL models exhibited chronic activation of the BCR-driven classical nuclear factor-{kappa}B (NF-{kappa}B) pathway, whereas insensitive cell lines displayed activation of the alternative NF-{kappa}B pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-{kappa}B pathway signaling components in ibrutinib-insensitive cell lines, and sequencing of 165 samples from patients with MCL identified recurrent mutations in TRAF2 or BIRC3 in 15% of these individuals. Although they are associated with insensitivity to ibrutinib, lesions in the alternative NF-{kappa}B pathway conferred dependence on the protein kinase NIK (also called mitogen-activated protein 3 kinase 14 or MAP3K14) both in vitro and in vivo. Thus, NIK is a new therapeutic target for MCL treatment, particularly for lymphomas that are refractory to BCR pathway inhibitors. Our findings reveal a pattern of mutually exclusive activation of the BCR-NF-{kappa}B or NIK-NF-{kappa}B pathways in MCL and provide critical insights into patient stratification strategies for NF-{kappa}B pathway-targeted agents.
ISSN:1078-8956
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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