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

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

doi:10.18632/oncotarget.7687

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.

Highlights

The t(12;21)(p13;q22) chromosomal translocation gives rise to the ETV6/RUNX1 (TEL/AML1) fusion gene.ETV6/RUNX1 represents the most abundant translocation product in pediatric cancers with an incidence of up to 25% in children with B lymphoblastic leukemia (B-ALL) [1, 2]
ETV6/RUNX1 transgenic (E/Rtg) mice were bred with Vav-B cell lymphoma 2 (BCL2) transgenic mice [35] to assess whether the antiapoptotic protein BCL2 would cooperate with ETV6/RUNX1 to initiate leukemia
We observed that E/Rtg;BCL2 transgene (BCL2tg) mice exhibited a significantly shorter lifespan compared to BCL2tg mice (221 vs. 293 days median survival) (Figure 1A)

Summary

Introduction

ETV6/RUNX1 represents the most abundant translocation product in pediatric cancers with an incidence of up to 25% in children with B lymphoblastic leukemia (B-ALL) [1, 2]. ETV6/ RUNX1 positive B-ALL is diagnosed during childhood, with a peak incidence between three and six years of age [10]. This suggests that the translocation product alone is not sufficient for leukemia onset [11,12,13]. In line with other animal models [14, 15, 17,18,19,20] we failed to detect leukemia in our transgenic mice, but we observed abnormal B cell maturation associated with increased ROS levels in the B cell compartment as well as increased frequency of pre- and immature B cells [16]

Methods

Results

Conclusion