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Oncotarget. 2016 Mar 15;7(11):12191-205. doi: 10.18632/oncotarget.7687.

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

Author information

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.

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:

BCL2; ETV6/RUNX1; Immune response; Immunity; Immunology and Microbiology Section; autoimmunity; glomerulonephritis; lymphoma

PMID:
26919255
PMCID:
PMC4914278
DOI:
10.18632/oncotarget.7687
[Indexed for MEDLINE]
Free PMC Article

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