Abstract
MYC and RUNX oncogenes each trigger p53‐mediated failsafe responses when overexpressed in vitro and collaborate with p53 deficiency in vivo. However, together they drive rapid onset lymphoma without mutational loss of p53. This phenomenon was investigated further by transcriptomic analysis of premalignant thymus from RUNX2/MYC transgenic mice. The distinctive contributions of MYC and RUNX to transcriptional control were illustrated by differential enrichment of canonical binding sites and gene ontology analyses. Pathway analysis revealed signatures of MYC, CD3, and CD28 regulation indicative of activation and proliferation, but also strong inhibition of cell death pathways. In silico analysis of discordantly expressed genes revealed Tnfsrf8/CD30, Cish, and Il13 among relevant targets for sustained proliferation and survival. Although TP53 mRNA and protein levels were upregulated, its downstream targets in growth suppression and apoptosis were largely unperturbed. Analysis of genes encoding p53 posttranslational modifiers showed significant upregulation of three genes, Smyd2, Set, and Prmt5. Overexpression of SMYD2 was validated in vivo but the functional analysis was constrained by in vitro loss of p53 in RUNX2/MYC lymphoma cell lines. However, an early role is suggested by the ability of SMYD2 to block senescence‐like growth arrest induced by RUNX overexpression in primary fibroblasts.
Highlights
The oncogenic potential of RUNX2 was first discovered through its identification as a target for transcriptional activation in a retroviral mutagenesis screen in transgenic mice overexpressing MYC in the T‐cell compartment (CD2‐MYC).[1]
A rationale for this selective targeting is that the Runx genes operate as “conditional” oncogenes, inducing growth arrest when activated in primary cells but driving tumor development when combined with MYC overexpression or loss of function of the p53 pathway.[9]
In support of this hypothesis, overexpression of RUNX2 alone is growth suppressive in early T‐cell development, blocking differentiation and proliferation at the β‐selection stage, but confers predisposition to lymphoma and collaborates strongly with germ‐line inactivation of p53.7,10 ectopic expression of any of the RUNX family induces senescence‐like growth arrest (SLGA) in primary mouse or human fibroblasts through a process that depends on the integrity of both the p19Arf/p53 and p16Cdkn2a/Rb arms of the tumor suppressor response.[11,12,13,14]
Summary
The oncogenic potential of RUNX2 was first discovered through its identification as a target for transcriptional activation in a retroviral mutagenesis screen in transgenic mice overexpressing MYC in the T‐cell compartment (CD2‐MYC).[1] It was subsequently shown that any of the three murine Runx family genes can be selected for activation in this transgenic model,[2,3,4] suggesting a redundant oncogenic role for RUNX overexpression in the context of MYC‐induced lymphoma. Our findings indicate that p53 is upregulated but functionally quiescent in prelymphoma cells, suggesting that posttranslational control of the p53 activity is important for potent MYC/RUNX oncogenic synergy
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