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

in eLife by Anne Fajac, Iva Simeonova, Julia Leemput, Marc Gabriel, Aurélie Morin, Vincent Lejour, Annaïg Hamon, Jeanne Rakotopare, Wilhelm Vaysse-Zinkhöfer, Eliana Eldawra, Marina Pinskaya, Antonin Morillon, Jean-Christophe Bourdon, Boris Bardot, Franck Toledo

TLDR

  • The study investigates how a specific part of a gene called p53 affects the development of a type of cancer called lymphoma in mice. The researchers found that when a specific part of the p53 gene was missing, male mice were no longer protected from developing lymphoma. The study also identified a specific protein that helps prevent lymphoma and a specific factor that is important for male mice to develop lymphoma. These findings provide insights into how the p53 gene works and how it affects the development of lymphoma in males and females.

Abstract

Thegene encodes several isoforms of elusive biological significance. Here, we show that mice lacking thealternatively 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 inmales compared tomales, but also compared toandfemales. Pre-tumoral splenic cells frommales exhibited a higher expression ofencoding an atypical chemokine receptor with tumor suppressive effects. We identifiedas a p53 target gene whose p53-mediated transactivation is inhibited by estrogens, and as a male-specific factor of good prognosis relevant for murine-induced and human Burkitt lymphomas. Furthermore, the knockout ofincreased 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.

Overview

  • The study investigates the role of alternatively spliced (AS) exon in p53-mediated protection against Myc-induced B-cell lymphomas in mice. The hypothesis being tested is whether the absence of the AS exon affects the male-specific protection against lymphomas. The methodology used includes the generation of mice lacking the AS exon, and the evaluation of lymphomagenesis in males, females, and controls. The primary objective of the study is to determine the impact of the AS exon on lymphomagenesis and the male-specific protection against lymphomas. The study aims to provide insights into the functional relevance of alternatively spliced p53 isoforms and sex disparities in Myc-driven lymphomagenesis.

Comparative Analysis & Findings

  • The study found that males lacking the AS exon had unexpectedly lost male-specific protection against Myc-induced B-cell lymphomas. Lymphomagenesis was delayed in males compared to females, but also compared to controls. Pre-tumoral splenic cells from males exhibited a higher expression of encoding an atypical chemokine receptor with tumor suppressive effects. The knockout ofincreased the chemokine-guided migration of Burkitt lymphoma cells. These findings suggest that the AS exon plays a crucial role in p53-mediated protection against lymphomas and that male-specific protection against lymphomas is affected by the absence of the AS exon. The study also identified 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-induced and human Burkitt lymphomas. These findings provide insights into the functional relevance of alternatively spliced p53 isoforms and sex disparities in Myc-driven lymphomagenesis.

Implications and Future Directions

  • The study's findings suggest that the AS exon plays a crucial role in p53-mediated protection against lymphomas and that male-specific protection against lymphomas is affected by the absence of the AS exon. The study identifies a p53 target gene whose p53-mediated transactivation is inhibited by estrogens and a male-specific factor of good prognosis relevant for murine-induced and human Burkitt lymphomas. These findings provide insights into the functional relevance of alternatively spliced p53 isoforms and sex disparities in Myc-driven lymphomagenesis. Future research directions could include the investigation of the role of the AS exon in other types of lymphomas and the development of targeted therapies to modulate the expression of the AS exon and p53-mediated transactivation in lymphomas. The study also highlights the importance of considering sex disparities in lymphomagenesis and the development of personalized therapies that take into account the unique biological characteristics of males and females.
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