Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies

Abstract

Activation of the classical nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway is a common molecular event observed in both human and canine diffuse large B-cell lymphoma (DLBCL). Although the oncogenic potential of the alternative NFκB pathway (ANFκBP) has also been recently identified in DLBCL, its precise role in tumor pathogenesis and potential as a treatment target is understudied. We hypothesized that up-regulation of the ANFκBP plays an important role in the proliferation and survival of canine DLBCL cells, and we demonstrate that the ANFκBP is constitutively active in primary canine DLBCL samples and a cell line (CLBL1). We further demonstrate that a small interfering RNA inhibits the activation of the NFκB pathway and induces apoptosis in canine DLBCL cells. In conclusion, the ANFκBP facilitates survival of canine DLBCL cells, and thus, dogs with spontaneous DLBCL can provide a useful large animal model to study therapies targeting the ANFκBP.

Keywords:

• Diffuse large B-cell lymphoma
• alternative NFκB pathway
• canine model
• targeting therapy
• comparative pathology

Acknowledgements

This study was supported in part by Morris Animal Foundation grants D10CA-501 (JFM, KLT, MB), D12CA-302 (DI) and D13CA-033 (DI and JFM), a Masonic Cancer Center Hematologic Malignancy Innovations Award (MAL, VB, LJB, JFM), and a grant from the Skippy Frank Fund for Life Sciences and Translational Research (DI and JFM), and grant CHF-1889G from the Golden Retriever Foundation and the AKC Canine Health Foundation (JM, KLT, MB). The Odyssey immunoblotting core was supported through the Comprehensive Cancer Center Support Grant to the Masonic Cancer Center, University of Minnesota (P30 CA077598). JFM is supported by the Alvin and June Perlman Chair in Animal Oncology. The authors gratefully acknowledge donors to the Animal Cancer Care and Research Program of the University of Minnesota that helped support this project. The authors acknowledge Kiersten Jensen for technical help and Mitzi Lewellen for assistance with inventory and database management.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at http://dx.doi.org/10.1080/10428194.2016.1260122.