The Runx genes as dominant oncogenes.
We have shown previously that Runx2 is a frequent target (approximately equal to 30%) for proviral insertion in murine leukemia virus (MLV) induced T cell tumors in CD2-MYC transgenic mice. Further investigation of a large panel of these tumors revealed that a small number also contain insertions at either Runx3 or Runx1. None of the tumors contained insertions at more than one family member, but in each case proviral insertion was associated with a high level of expression from the upstream (P1) promoter of the respective target gene. Moreover, we confirmed that transcriptional activation of Runx1 does not affect the integrity of the coding sequence, as previously observed for Runx2. These observations suggest that the three Runx genes act as functionally redundant oncogenes in T-cell lymphoma development. To explore the oncogenic potential of Runx2 further we created transgenic mice that over-express this gene in the T cell compartment. These CD2-Runx2 animals show a preneoplastic enlargement of the CD8 immature single positive (ISP) thymocyte pool and develop lymphomas at a low incidence. Although the CD8 ISP population is greatly increased, unlike their wild type counterparts these cells are largely non-cycling. Co-expression of c-MYC in this lineage accentuates the CD8 ISP skew and induces rapid tumor development, confirming the potent synergy that exists between these two oncogenes. Experiments designed to understand the nature of the observed synergy are ongoing and are based on the hypothesis that Runx2 may exert a survival effect in c-MYC expressing tumors in vivo while c-MYC may rescue cells from the antiproliferative effects of Runx2. The oncogenic potential of Runx1 is also being assessed using primary murine embryonic fibroblasts (MEFs). These studies have revealed that while Runx1 exerts a growth suppressive effect in wild type cells a growth promoting effect is seen in the absence of p53, suggesting that the Runx genes may harbor latent oncogene-like properties.
Molecular Oncology Laboratory, Institute of Comparative Medicine, University of Glasgow Veterinary School, Glasgow G61 1QH, UK. E.R.Cameron@vet.gla.ac.uk
Ewan R
ER
Cameron
Karen
K
Blyth
Linda
L
Hanlon
Anna
A
Kilbey
Nancy
N
Mackay
Monica
M
Stewart
Anne
A
Terry
Francois
F
Vaillant
Sandy
S
Wotton
James C
JC
Neil
D000818:Animals; D050659:Core Binding Factor Alpha 1 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins / Q000235:genetics*; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D013601:T-Lymphocytes / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*
D050659:Core Binding Factor Alpha 1 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C493729:Runx3 protein, human; D014157:Transcription Factors