Mutant mice lacking alternatively spliced p53 isoforms unveil <i>Ackr4</i> as a male-specific prognostic factor in Myc-driven B-cell lymphomas.

Abstract

The <i>Trp53</i> gene encodes several isoforms of elusive biological significance. Here, we show that mice lacking the <i>Trp53</i> alternatively 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 <i>Trp53^+/+Eμ-Myc</i> males compared to <i>Trp53^ΔAS/ΔAS Eμ-Myc</i> males, but also compared to <i>Trp53^+/+Eμ-Myc</i> and <i>Trp53^ΔAS/ΔAS Eμ-Myc</i> females. Pre-tumoral splenic cells from <i>Trp53^+/+Eμ-Myc</i> males exhibited a higher expression of <i>Ackr4,</i> encoding an atypical chemokine receptor with tumor suppressive effects. We identified <i>Ackr4</i> as a p53 target gene whose p53-mediated transactivation is inhibited by estrogens, and as a male-specific factor of good prognosis relevant for murine <i>Eμ-Myc</i>-induced and human Burkitt lymphomas. Furthermore, the knockout of <i>ACKR4</i> increased 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.