Oncotarget

Research Papers: Immunology:

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

Eva Bauer, Michaela Schlederer, Ruth Scheicher, Jaqueline Horvath, Petra Aigner, Ana-Iris Schiefer, Renate Kain, Heinz Regele, Gregor Hoermann, Günter Steiner, Lukas Kenner, Veronika Sexl, Andreas Villunger, Richard Moriggl and Dagmar Stoiber _

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Oncotarget. 2016; 7:12191-12205. https://doi.org/10.18632/oncotarget.7687

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Abstract

Eva Bauer1, Michaela Schlederer1,2, Ruth Scheicher3, Jaqueline Horvath1,4, Petra Aigner1, Ana-Iris Schiefer2, Renate Kain2, Heinz Regele2, Gregor Hoermann5, Günter Steiner6,7, Lukas Kenner1,2,8, Veronika Sexl3, Andreas Villunger9,10, Richard Moriggl1,5,11 and Dagmar Stoiber1,4

1 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

2 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria

3 Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria

4 Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

5 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

6 Cluster Arthritis and Rehabilitation, Ludwig Boltzmann Society, Vienna, Austria

7 Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

8 Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria

9 Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria

10 Tyrolean Cancer Research Institute, Innsbruck, Austria

11 Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria

Correspondence to:

Dagmar Stoiber, email:

Keywords: ETV6/RUNX1, BCL2, glomerulonephritis, lymphoma, autoimmunity, Immunology and Microbiology Section, Immune response, Immunity

Received: September 11, 2015 Accepted: January 31, 2016 Published: February 23, 2016

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.


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