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Oncogene. 2016 Dec 1;35(48):6223-6234. doi: 10.1038/onc.2016.155. Epub 2016 May 9.

FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma.

Author information

1
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
2
Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
3
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
4
Wisconsin Institute for Discovery and Laboratory of Genetics, University of Wisconsin, Madison, WI, USA.
5
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
6
Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
7
Division of Preclinical Innovation, National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Bethesda, MD, USA.
8
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Abstract

Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.

PMID:
27157620
PMCID:
PMC5102814
DOI:
10.1038/onc.2016.155
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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