title: 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.
authors.affiliation: a Department of Veterinary Clinical Sciences, College of Veterinary Medicine , University of Minnesota , St. Paul , MN , USA.|b Masonic Cancer Center , University of Minnesota , Minneapolis , MN , USA.
authors.forename: Davis M
authors.initials: DM
authors.lastname: Seelig
authors.affiliation: a Department of Veterinary Clinical Sciences, College of Veterinary Medicine , University of Minnesota , St. Paul , MN , USA.|b Masonic Cancer Center , University of Minnesota , Minneapolis , MN , USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.affiliation: c The University of Minnesota Biological Materials Procurement Network (BioNet), University of Minnesota , Minneapolis , MN , USA.
authors.forename: Colleen L
authors.initials: CL
authors.lastname: Forster
authors.affiliation: a Department of Veterinary Clinical Sciences, College of Veterinary Medicine , University of Minnesota , St. Paul , MN , USA.
authors.forename: Una A
authors.initials: UA
authors.lastname: Yoon
authors.affiliation: d Department of Molecular Biomedical Sciences, College of Veterinary Medicine , Center for Comparative Medicine and Translational Research, North Carolina State University , Raleigh , NC , USA.|e Cancer Genetics Program , University of North Carolina Lineberger Comprehensive Cancer Center , Raleigh , NC , USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Breen
authors.affiliation: b Masonic Cancer Center , University of Minnesota , Minneapolis , MN , USA.|f Department of Medicine, Division of Hematology, Oncology, and Transplantation, School of Medicine , University of Minnesota , Minneapolis , MN , USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Burns
authors.affiliation: b Masonic Cancer Center , University of Minnesota , Minneapolis , MN , USA.|f Department of Medicine, Division of Hematology, Oncology, and Transplantation, School of Medicine , University of Minnesota , Minneapolis , MN , USA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Bachanova
authors.affiliation: g Broad Institute of MIT and Harvard , Cambridge , MA , USA.|h Department of Medical Biochemistry and Microbiology, Science for Life Laboratory , Uppsala University , Uppsala , Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.affiliation: i Department of Veterinary Population Medicine, College of Veterinary Medicine , University of Minnesota , St. Paul , MN , USA.|j Stem Cell Institute , University of Minnesota , Minneapolis , MN , USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Brien
authors.affiliation: k Department of Pathology , University of Washington , Seattle , WA , USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Schmechel
authors.affiliation: k Department of Pathology , University of Washington , Seattle , WA , USA.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Rizzardi
authors.affiliation: a Department of Veterinary Clinical Sciences, College of Veterinary Medicine , University of Minnesota , St. Paul , MN , USA.|b Masonic Cancer Center , University of Minnesota , Minneapolis , MN , USA.|i Department of Veterinary Population Medicine, College of Veterinary Medicine , University of Minnesota , St. Paul , MN , USA.|j Stem Cell Institute , University of Minnesota , Minneapolis , MN , USA.|l Center for Immunology , University of Minnesota , Minneapolis , MN , USA.
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
authors.affiliation: b Masonic Cancer Center , University of Minnesota , Minneapolis , MN , USA.|m Department of Laboratory Medicine and Pathology, Division of Hematopathology, School of Medicine , University of Minnesota , Minneapolis , MN , USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Linden
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B
keywords: Diffuse large B-cell lymphoma; alternative NFκB pathway; canine model; comparative pathology; targeting therapy