title: NF-kappaB2 mutation targets TRAF1 to induce lymphomagenesis.
abstract: The NF-kappaB2 gene is recurrently mutated in human lymphoid malignancies. However, a causal relationship between NF-kappaB2 mutation and lymphomagenesis has not been established. It is also unclear how the mutation may lead to lymphoid malignancies. We report the generation of transgenic mice with targeted expression of p80HT, a lymphoma-associated NF-kappaB2 mutant, in lymphocytes. The transgenic mice display a marked expansion of peripheral B cell populations and develop predominantly small B cell lymphomas. p80HT expression has no apparent effect on the proliferation of B cells, but renders them specifically resistant to apoptosis induced by cytokine deprivation and mitogenic stimulation. Lymphocytes and lymphoma cells from p80HT mice express high levels of TRAF1, an antiapoptotic protein also implicated in lymphoid malignancies. p80HT binds the TRAF1 promoter in vivo and activates TRAF1 transcription. Moreover, TRAF1 knockdown abrogates the antiapoptotic activity of p80HT and TRAF1 deficiency reestablishes B cell homeostasis in p80HT mice. These findings demonstrate NF-kappaB2 mutation as an oncogenic event in vivo and suggest a molecular pathway for TRAF1 activation in the pathogenesis of lymphomas.
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA.
authors.forename: Baochun
authors.initials: B
authors.lastname: Zhang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Tai
authors.initials: T
authors.lastname: Li
authors.forename: Erdyni N
authors.initials: EN
authors.lastname: Tsitsikov
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000502:physiology; D002470:Cell Survival; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000473:pathology / Q000502:physiology; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D052003:NF-kappa B p52 Subunit / Q000235:genetics*; D016133:Polymerase Chain Reaction; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D052003:NF-kappa B p52 Subunit; D047992:TNF Receptor-Associated Factor 2