The Runx genes (Runx1, 2 and 3) regulate cell fate in development and can operate as oncogenes or tumour suppressors in cancer. We aim to elucidate this dualistic behaviour and identify safe therapeutic targets in the relevant downstream pathways.
Ectopic expression of Runx in primary fibroblasts induces premature senescence1, whilst analysis of Runx2-/- fibroblasts indicate that these genes are central components of this failsafe process2.
We have identified loss of p53/Ink4a or ectopic expression of Myc as key events in converting the ectopic Runx signal from growth suppression to oncogenesis in fibroblasts and lymphoid cells respectively1,3, and we have recently shown that enzymes regulating sphingolipid metabolism are important for fibroblast survival 4. We now identify Sgpp1, a key enzyme in sphingolipid metabolism as a direct transcriptional target of the Runx protein family in lymphoid cells. Moreover, we demonstrate cooperativity at the Sgpp1 promoter by Myc and Runx extending evidence of an important link between transcription factor oncogenes and lipid signalling pathways.
RUNX1 fusion oncoproteins found in human leukaemia are heterogeneous with regard to their ability to induce SLGA in human fibroblasts5. The RUNX1-ETO and RUNX1-ETO9a fusion oncoproteins associated with acute myeloid leukaemia retain this activity although downstream pathways overlap only partially with RUNX1. In contrast, the TEL/RUNX1 fusion oncoprotein inhibits premature senescence by a process that requires sumoylation of the TEL domain. Notably, all RUNX1 fusion proteins have lost the capacity to regulate sphingolipid enzymes6, suggesting a possible basis for the selective retention and expression of the non-translocated allele in t(12;21) and t(8;21) leukaemias.
Our findings suggest further that pathways downstream of endogenous Runx may be useful therapeutic targets in tumours with or without RUNX1 fusions.