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Type of publication: Journal Article
Type of document: Full Paper

Year: 2016

Authors: Bauer, E; Schlederer, M; Scheicher, R; Horvath, J; Aigner, P; Schiefer, AI; Kain, R; Regele, H; Hoermann, G; Steiner, G; Kenner, L; Sexl, V; Villunger, A; Moriggl, R; Stoiber, D

Title: Cooperation of ETV6/RUNX1 and BCL2 enhances immunoglobulin production and accelerates glomerulonephritis in transgenic mice.

Source: Oncotarget. 2016; 7(11):12191-12205



Authors Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard
Scheicher Ruth
Sexl Veronika

Vetmed Research Units
Institute of Pharmacology and Toxicology
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics


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.

Keywords Pubmed: Animals
Core Binding Factor Alpha 2 Subunitgeneticsimmunology
Glomerulonephritisgeneticsimmunology
Humans
Immunoglobulinsbiosynthesisimmunology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Proto-Oncogene Proteins c-bcl-2biosynthesisimmunology
Proto-Oncogene Proteins c-etsgeneticsimmunology
Repressor Proteinsgeneticsimmunology

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