Collaboration of MYC and RUNX2 in lymphoma simulates T‐cell receptor signaling and attenuates p53 pathway activity

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. In this paper, we use transcriptomic analysis to investigate the mechanisms by which MYC and RUNX oncogenes cooperate to drive rapid lymphomagenesis without mutational loss of p53. We show that this gene combination activates pathways to simulate the successful transit of cells through T‐cell repertoire selection. We also show that RUNX2 and MYC collaborate to upregulate the methyltransferase SMYD2, shown by the presence of anchored RUNX/MYC sites, thus functionally inactivating p53 at the posttranslational level.