Mutant mice lacking alternatively spliced p53 isoforms unveil Ackr4 as a male-specific prognostic factor in Myc-driven B-cell lymphomas
The Trp53 gene encodes several isoforms of elusive biological significance. Here, we show that mice lacking the Trp53 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 Trp53 +/+ Eμ-Myc males compared to Trp53 ΔAS/ΔAS Eμ-Myc males, but also compared to Trp53 +/+ Eμ-Myc and Trp53 ΔAS/ΔAS Eμ-Myc females. Pre-tumoral splenic cells from Trp53 +/+ Eμ-Myc males exhibited a higher expression of Ackr4, encoding an atypical chemokine receptor with tumor suppressive effects. We identified Ackr4 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 Eμ-Myc -induced and human Burkitt lymphomas. Furthermore, the knockout of ACKR4 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.
Authors
- Iva Simeonova (ORCID: https://orcid.org/0000-0001-8277-6547)
- Marc Gabriel (ORCID: https://orcid.org/0000-0003-1489-5944)
- Anne Fajac
- Wilhelm Vaysse-Zinkhöfer (ORCID: https://orcid.org/0000-0001-6734-1676)
- Marina Pinskaya (ORCID: https://orcid.org/0000-0003-1992-0264)
- Julia Leemput (ORCID: https://orcid.org/0000-0001-8732-0741)
- Vincent Lejour (ORCID: https://orcid.org/0000-0002-2797-1507)
- Antonin Morillon (ORCID: https://orcid.org/0000-0002-0575-5264)
- Franck Toledo (ORCID: https://orcid.org/0000-0003-3798-4106)
- Jean‐Christophe Bourdon (ORCID: https://orcid.org/0000-0003-4623-9386)
- Aurélie Morin (ORCID: https://orcid.org/0000-0003-2048-6805)
- Annaïg Hamon (ORCID: https://orcid.org/0000-0002-1662-1405)
- Boris Bardot (ORCID: https://orcid.org/0000-0003-4976-9593)
- Jeanne Rakotopare (ORCID: https://orcid.org/0009-0005-1218-4921)
- Eliana Eldawra
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Dundee (GB)
- Université Paris Sciences et Lettres (FR)
- Ninewells Hospital (GB)
- Sorbonne Université (FR)
- Dynamique de l'information génétique : bases fondamentales et cancer (FR)
- Institut Curie (FR)
Publication Details
- Journal
- eLife
- Published
- 2024-09-19
- DOI
- https://doi.org/10.7554/elife.92774.3
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Fondation de France