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

Oncogene volume 35, pages 6223–6234 (2016)Cite this article

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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.

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Acknowledgements

We thank Dr Louis Staudt for providing the reagents, Dr Sameer Mathur for providing peripheral blood mononuclear cells, Dr Wei Huang for helping with analysis of immunohistochemical data, Drs Debra Bloom and Peiman Hematti for providing CD40, BAFF and BAFF receptor antibody, and Kirsti Walker for monitoring xenografted mice. This work was supported by the UW-Madison Start-up funds, KL2 Scholar Award (UL1TR0000427 and KL2TR000428), and NIH R01 CA187299 to LR, the MACC fund and the National Institutes of Health/National Cancer Institute (K08 CA174750) to CMC, the UW-Madison Start-up funds and USDA National Institute of Food and Agriculture (Hatch 1002874) to XZ, and the UW Forward Lymphoma Fund. We thank the University of Wisconsin Carbone Cancer Center (UWCCC) for the funds to complete this project. This work was also supported in part by NIH/NCI P30 CA014520- UW Comprehensive Cancer Center Support.

Accession Codes

All sequencing data were deposited into GEO with the accession number GSE80563.

Author contributions

LR designed research; LR, CMC, DTY, SM and BSK conceived and supervised the project; YL, MNB, LR, JW, KMG, LL, SQ, NP and SM. W-D performed research. LL, XZ and JCE analyzed data; CJT contributed reagents and intellectual input; LR, YL and MNB wrote the paper.

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Author notes

  1. B S Kahl

    Present address: 10Current address: Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.,

  2. Y Li and M N Bouchlaka: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Y Li, J Wolff, K M Grindle, N Pflum, P Jobin, B S Kahl & L Rui

  2. Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Y Li, M N Bouchlaka, K M Grindle, B S Kahl, S M Wuerzberger-Davis, S Miyamoto, D T Yang, C M Capitini & L Rui

  3. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    M N Bouchlaka & C M Capitini

  4. Wisconsin Institute for Discovery and Laboratory of Genetics, University of Wisconsin, Madison, WI, USA

    L Lu, S Qian & X Zhong

  5. Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    J C Eickhoff

  6. Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    S M Wuerzberger-Davis & S Miyamoto

  7. Division of Preclinical Innovation, National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Bethesda, MD, USA

    C J Thomas

  8. Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    D T Yang

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Li, Y., Bouchlaka, M., Wolff, J. et al. FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma. Oncogene 35, 6223–6234 (2016). https://doi.org/10.1038/onc.2016.155

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