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

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


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.

MeSH terms

  • Animals
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / immunology*
  • Glomerulonephritis / genetics
  • Glomerulonephritis / immunology*
  • Humans
  • Immunoglobulins / biosynthesis*
  • Immunoglobulins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / immunology*
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / immunology*
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology*


  • BCL2 protein, human
  • Core Binding Factor Alpha 2 Subunit
  • ETS translocation variant 6 protein
  • Immunoglobulins
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-ets
  • Repressor Proteins
  • Runx1 protein, mouse