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Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
Published on: March 30, 2018
Mutant mice lacking alternatively spliced p53 isoforms unveil Ackr4 as a male-specific prognostic factor in
Anne Fajac1,2,3,4, Iva Simeonova1,2,3,4, Julia Leemput1,2,3,4
1Genetics of Tumor Suppression, Institut Curie, Paris, France.
Abstract:
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 males compared to Trp53 males, but also compared to Trp53 and Trp53 females. Pre-tumoral splenic cells from Trp53 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.
Insights
Alternatively spliced Trp53 isoforms offer male-specific protection against Myc-induced lymphomas. Loss of these isoforms, alongside estrogen inhibition of Ackr4, reveals sex disparities in lymphoma development.
Area of Science:
- Molecular Biology
- Immunology
- Oncology
Background:
- The Trp53 gene produces multiple isoforms with unclear biological roles.
- p53 isoforms, particularly those with an alternatively spliced (AS) C-terminus, are implicated in cellular regulation.
Purpose of the Study:
- To investigate the role of Trp53 alternatively spliced (AS) isoforms in Myc-induced B-cell lymphomagenesis.
- To elucidate the sex-specific differences in lymphoma development related to Trp53 isoforms.
Main Methods:
- Generation of mice lacking the Trp53 AS exon.
- Analysis of lymphomagenesis in Trp53 mutant mice.
- Gene expression analysis (Ackr4) in splenic cells.
- Investigation of estrogen's effect on p53-mediated Ackr4 transactivation.
- Assessment of ACKR4 knockout impact on lymphoma cell migration.
Main Results:
- Mice lacking Trp53 AS exon lost male-specific protection against Myc-induced B-cell lymphomas.
- Lymphomagenesis was delayed in Trp53 mutant males compared to controls and Trp53 mutant females.
- Higher Ackr4 expression was observed in pre-tumoral splenic cells from Trp53 mutant males.
- Estrogen inhibits p53-mediated transactivation of Ackr4, a male-specific tumor suppressor.
- ACKR4 knockout enhanced lymphoma cell migration, indicating its role in chemokine-guided movement.
Conclusions:
- Alternatively spliced Trp53 isoforms are functionally relevant, providing male-specific protection against Myc-driven lymphomas.
- Ackr4 acts as a male-specific tumor suppressor, its activity modulated by estrogens.
- Sex disparities exist in Myc-driven lymphomagenesis, influenced by Trp53 isoforms and Ackr4.
- ACKR4 is a potential prognostic factor for murine and human lymphomas.
