title: Cooperation of ETV6/RUNX1 and BCL2 enhances immunoglobulin production and accelerates glomerulonephritis in transgenic mice.
abstract: The t(12;21) translocation generating the ETV6/RUNX1 fusion gene represents the most frequent chromosomal rearrangement in childhood leukemia. Presence of ETV6/RUNX1 alone is usually not sufficient for leukemia onset, and additional genetic alterations have to occur in ETV6/RUNX1-positive cells to cause transformation. We have previously generated an ETV6/RUNX1 transgenic mouse model where the expression of the fusion gene is restricted to CD19-positive B cells. Since BCL2 family members have been proposed to play a role in leukemogenesis, we investigated combined effects of ETV6/RUNX1 with exogenous expression of the antiapoptotic protein BCL2 by crossing ETV6/RUNX1 transgenic animals with Vav-BCL2 transgenic mice. Strikingly, co-expression of ETV6/RUNX1 and BCL2 resulted in significantly shorter disease latency in mice, indicating oncogene cooperativity. This was associated with faster development of follicular B cell lymphoma and exacerbated immune complex glomerulonephritis. ETV6/RUNX1-BCL2 double transgenic animals displayed increased B cell numbers and immunoglobulin titers compared to Vav-BCL2 transgenic mice. This led to pronounced deposition of immune complexes in glomeruli followed by accelerated development of immune complex glomerulonephritis. Thus, our study reveals a previously unrecognized synergism between ETV6/RUNX1 and BCL2 impacting on malignant disease and autoimmunity.
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Bauer
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Ruth
authors.initials: R
authors.lastname: Scheicher
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Jaqueline
authors.initials: J
authors.lastname: Horvath
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Aigner
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ana-Iris
authors.initials: AI
authors.lastname: Schiefer
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Kain
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Regele
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Gregor
authors.initials: G
authors.lastname: Hoermann
authors.affiliation: Cluster Arthritis and Rehabilitation, Ludwig Boltzmann Society, Vienna, Austria.|Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.|Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.|Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stoiber
mesh_terms: D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000276:immunology*; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000276:immunology*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D007136:Immunoglobulins; D019253:Proto-Oncogene Proteins c-bcl-2; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C000595707:BCL2 protein, human; C493726:Runx1 protein, mouse
keywords: BCL2; ETV6/RUNX1; Immune response; Immunity; Immunology and Microbiology Section; autoimmunity; glomerulonephritis; lymphoma