Mutant mice lacking alternatively spliced p53 isoforms unveilAckr4as a male-specific prognostic factor in Myc-driven B-cell lymphomas

TheTrp53gene encodes several isoforms of elusive biological significance. Here we show that mice lacking theTrp53Alternatively Spliced (AS) exon, thereby expressing the canonical p53 protein but not isoforms with the AS C-terminus, have unexpectedly lost a male-specific protection against Myc-induced B-cell lymphomas. Lymphomagenesis was delayed in p53^+/+Eμ-Myc males compared to p53^ΔAS/ΔASEμ-Myc males, but also compared to p53^+/+Eμ-Myc and p53^ΔAS/ΔASEμ-Myc females. Pre-tumoral splenic cells from p53^+/+Eμ-Myc males exhibited a higher expression ofAckr4,encoding an atypical chemokine receptor with tumor suppressive effects. We identifiedAckr4as a p53 target gene whose p53-mediated transactivation is inhibited by estrogens, and as a male-specific factor of good prognosis relevant for murine Eμ-Myc-induced and human Burkitt lymphomas. Furthermore, the knockout ofACKR4increased the chemokine-guided migration of Burkitt lymphoma cells. These data demonstrate the functional relevance of alternatively spliced p53 isoforms and reveal sex disparities in Myc-driven lymphomagenesis.