Induction of p53-mediated apoptosis by azacitidine in patient-derived xenograft follicular helper T-cell lymphoma model
Follicular helper T-cell lymphoma (TFHL) is the most common non-cutaneous T-cell lymphoma in the Western world and is associated with a poor prognosis. Neoplastic cells rely heavily on the tumor microenvironment, demonstrated by the absence of TFHL-derived cell lines, which hinders therapeutic progress. To overcome this limitation, we developed and characterized patient-derived xenograft TFHL (TFHL-PDXs). Fifteen TFHLs were implanted into immunodeficient mice, generating nine PDXs. The tumor microenvironment was detected in the first passage but progressively disappeared in subsequent passages. TET2 mutations persisted in all cases and TFHL-specific mutations were observed in most. The models were treated with azacitidine and patient sensitivity was fully recapitulated. To elucidate the mechanism of action of azacitidine, we analyzed the differences in DNA methylation and gene expression in six TFHL-PDX models. Global DNA hypomethylation occurred in azacitidine-treated cells in drug-sensitive models but not in the resistant ones. DNA hypomethylation was associated with global upregulation of gene expression, including that of various cancer-related pathways, suggestive of p53-pathway-mediated cytotoxicity. Overall, the PDXs recapitulated TFHL features and exhibited sensitivity to azacitidine. They also made it possible to decipher the mechanism responsible for the effect of azacitidine, revealing the activation of p53-mediated apoptosis associated with DNA hypomethylation.
Authors
- Philippe Gaulard (ORCID: https://orcid.org/0000-0002-4243-905X)
- Vincent Alcazer (ORCID: https://orcid.org/0000-0003-1843-6286)
- Selcen Arı Yuka (ORCID: https://orcid.org/0000-0002-0028-2453)
- Anja Fischer (ORCID: https://orcid.org/0000-0002-7145-2544)
- Reiner Siebert (ORCID: https://orcid.org/0000-0001-7433-3703)
- Cyrielle Robe
- François Lemonnier (ORCID: https://orcid.org/0000-0001-6205-5419)
- Alexis Claudel (ORCID: https://orcid.org/0000-0002-7164-3930)
- Nouhoum Sako (ORCID: https://orcid.org/0000-0002-4071-0088)
- Marie‐Hélène Delfau‐Larue (ORCID: https://orcid.org/0000-0002-8010-2343)
- Nicolás Ortonne (ORCID: https://orcid.org/0000-0003-0111-7422)
- Alexis Gonon (ORCID: https://orcid.org/0000-0002-4967-743X)
- Gamze Tari (ORCID: https://orcid.org/0000-0001-9652-3751)
- Julie Naudet
- Mohamed Chour (ORCID: https://orcid.org/0009-0006-5755-4620)
- Diana Laure Mboumba
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Universität Ulm (DE)
- Université Paris-Est Créteil (FR)
- Paris-Est Sup (FR)
- Centre Hospitalier Universitaire Henri-Mondor (FR)
- Yıldız Technical University (TR)
- Hôpital Lyon Sud (FR)
- Hôpitaux Universitaires Henri-Mondor (FR)
- Lymphoma Study Association (FR)
- Institut Mondor de Recherche Biomédicale (FR)
- Centre International de Recherche en Infectiologie (FR)
Publication Details
- Journal
- Leukemia
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1038/s41375-025-02628-0
- Citations
- 3
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 4.41
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Institut National de la Santé et de la Recherche Médicale
- Bundesministerium für Bildung und Forschung
- Fondation ARC pour la Recherche sur le Cancer
- Université Paris-Est Créteil Val-de-Marne