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Original Articles: Research

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

Davis M. SeeligDepartment of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA; ;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA;

Daisuke ItoDepartment of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA; ;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA;

Colleen L. ForsterThe University of Minnesota Biological Materials Procurement Network (BioNet), University of Minnesota, Minneapolis, MN, USA;

Una A. YoonDepartment of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA;

Matthew BreenDepartment of Molecular Biomedical Sciences, College of Veterinary Medicine, Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, NC, USA; ;Cancer Genetics Program, University of North Carolina Lineberger Comprehensive Cancer Center, Raleigh, NC, USA;

Linda J. BurnsMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; ;Department of Medicine, Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Minneapolis, MN, USA;

Veronika BachanovaMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; ;Department of Medicine, Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Minneapolis, MN, USA;

Kerstin Lindblad-TohBroad Institute of MIT and Harvard, Cambridge, MA, USA; ;Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden;

Timothy D. O’BrienDepartment of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA; ;Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA;

Stephen C. SchmechelDepartment of Pathology, University of Washington, Seattle, WA, USA;

Anthony E. RizzardiDepartment of Pathology, University of Washington, Seattle, WA, USA;

Jaime F. ModianoDepartment of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA; ;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; ;Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA; ;Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA; ;Center for Immunology, University of Minnesota, Minneapolis, MN, USA;

Michael A. LindenMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; ;Department of Laboratory Medicine and Pathology, Division of Hematopathology, School of Medicine, University of Minnesota, Minneapolis, MN, USACorrespondence[email protected]

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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:

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.

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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

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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

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