Cooperation of ETV6/RUNX1 and BCL2 enhances immunoglobulin production and accelerates glomerulonephritis in transgenic mice.
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.
['Bauer|Eva|E|', 'Schlederer|Michaela|M|', 'Scheicher|Ruth|R|', 'Horvath|Jaqueline|J|', 'Aigner|Petra|P|', 'Schiefer|Ana-Iris|AI|', 'Kain|Renate|R|', 'Regele|Heinz|H|', 'Hoermann|Gregor|G|', 'Steiner|Günter|G|', 'Kenner|Lukas|L|', 'Sexl|Veronika|V|', 'Villunger|Andreas|A|', 'Moriggl|Richard|R|', 'Stoiber|Dagmar|D|']
D000818:Animals D050676:Core Binding Factor Alpha 2 Subunit D005921:Glomerulonephritis D006801:Humans D007136:Immunoglobulins D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D019253:Proto-Oncogene Proteins c-bcl-2 D050783:Proto-Oncogene Proteins c-ets D012097:Repressor Proteins
ETV6/RUNX1 BCL2 glomerulonephritis lymphoma Immunity autoimmunity Immune response Immunology and Microbiology Section