Runx2 disruption promotes immortalization and confers resistance to oncogene-induced senescence in primary murine fibroblasts.

The Runx genes play paradoxical roles in cancer where they can function either as dominant oncogenes or tumor suppressors according to context. We now show that the ability to induce premature senescence in primary murine embryonic fibroblasts (MEF) is a common feature of all three Runx genes. However, ectopic Runx-induced senescence contrasts with Ras oncogene-induced senescence, as it occurs directly and lacks the hallmarks of proliferative stress.

RUNX1 transformation of primary embryonic fibroblasts is revealed in the absence of p53.

The mammalian Runx gene family (Runx1-3) are transcription factors that play essential, lineage-specific roles in development. A growing body of evidence implicates these genes as mutational targets in cancer where, in different contexts, individual family members have been reported to act as tumour suppressors, dominant oncogenes or mediators of metastasis. We are exploring these paradoxical observations by ectopic expression of RUNX genes in primary murine embryonic fibroblasts where, in common with a number of other dominant oncogenes, RUNX1 induces senescence-like growth arrest in the presence of an intact p19(ARF)-p53 pathway.

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.

Proviral insertion indicates a dominant oncogenic role for Runx1/AML-1 in T-cell lymphoma.

The RUNX1/AML1 gene is a frequent target for chromosomal translocations in human leukemia. The biological properties of the resulting fusion products and the finding that haploinsufficiency increases the risk of developing leukemia (W-J. Song et al.