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

Autor:	Fajac A; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Simeonova I; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Leemput J; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Gabriel M; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France.; Non Coding RNA, Epigenetic and Genome Fluidity, Institut Curie, Paris, France., Morin A; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Lejour V; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Hamon A; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Rakotopare J; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Vaysse-Zinkhöfer W; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Eldawra E; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Pinskaya M; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France.; Non Coding RNA, Epigenetic and Genome Fluidity, Institut Curie, Paris, France., Morillon A; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France.; Non Coding RNA, Epigenetic and Genome Fluidity, Institut Curie, Paris, France., Bourdon JC; School of Medicine, Ninewells Hospital, University of Dundee, Dundee, United Kingdom., Bardot B; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France., Toledo F; Genetics of Tumor Suppression, Institut Curie, Paris, France.; CNRS UMR3244, Paris, France.; Sorbonne University, Paris, France.; PSL Research University, Paris, France.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Sep 19; Vol. 13. Date of Electronic Publication: 2024 Sep 19.
DOI:	10.7554/eLife.92774
Abstrakt:	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. Competing Interests: AF, IS, JL, MG, AM, VL, AH, JR, WV, EE, MP, AM, JB, BB, FT No competing interests declared (© 2024, Fajac et al.)
Databáze:	MEDLINE
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