Oncotarget

Research Papers:

Azathioprine induction of tumors with microsatellite instability: risk evaluation using a mouse model

Sahra Bodo _, Magali Svrcek, Isabelle Sourrouille, Peggy Cuillières-Dartigues, Tatiana Ledent, Sylvie Dumont, Laetitia Dinard, Philippe Lafitte, Camille Capel, Ada Collura, Olivier Buhard, Kristell Wanherdrick, Alexandra Chalastanis, Virginie Penard-Lacronique, Bettina Fabiani, Jean-François Fléjou, Nicole Brousse, Laurent Beaugerie, Alex Duval and Martine Muleris

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Oncotarget. 2015; 6:24969-24977. https://doi.org/10.18632/oncotarget.4638

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Abstract

Sahra Bodo1,2, Magali Svrcek1,2,3, Isabelle Sourrouille1,2, Peggy Cuillières-Dartigues4, Tatiana Ledent1,2, Sylvie Dumont2,5, Laetitia Dinard1,2, Philippe Lafitte1,2, Camille Capel1,2, Ada Collura1,2, Olivier Buhard1,2, Kristell Wanherdrick1,2, Alexandra Chalastanis1,2, Virginie Penard-Lacronique6, Bettina Fabiani3, Jean-François Fléjou1,2,3, Nicole Brousse7, Laurent Beaugerie2,8, Alex Duval1,2, Martine Muleris1,2

1INSERM, UMR_S 938, CDR Saint-Antoine, Equipe « Instabilité des Microsatellites et Cancer », Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France

2Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France

3AP-HP, Hôpital Saint-Antoine, Service d'Anatomie Pathologique, F-75012 Paris, France

4AP-HP, Institut Gustave Roussy, Service d'Anatomie Pathologique, F-94805 Villejuif, France

5IFR 65, F-75012 Paris, France

6INSERM, U985, Institut Gustave Roussy, F-94805 Villejuif, France

7AP-HP, Hôpital Necker-Enfants Malades, Service d'Anatomie Pathologique, F-75015 Paris, France

8AP-HP, Hôpital Saint-Antoine, Service de Gastroentérologie, F-75012 Paris, France

Correspondence to:

Martine Muleris, e-mail: martine.muleris@inserm.fr

Keywords: pharmacogenetics, iatrogenic cancer, microsatellite instability, thiopurine tolerance, azathioprine

Received: March 20, 2015     Accepted: August 07, 2015     Published: August 17, 2015

ABSTRACT

Mismatch-repair (MMR)-deficient cells show increased in vitro tolerance to thiopurines because they escape apoptosis resulting from MMR-dependent signaling of drug-induced DNA damage. Prolonged treatment with immunosuppressants including azathioprine (Aza), a thiopurine prodrug, has been suggested as a risk factor for the development of late onset leukemias/lymphomas displaying a microsatellite instability (MSI) phenotype, the hallmark of a defective MMR system. We performed a dose effect study in mice to investigate the development of MSI lymphomas associated with long term Aza treatment. Over two years, Aza was administered to mice that were wild type, null or heterozygous for the MMR gene Msh2. Ciclosporin A, an immunosuppressant with an MMR-independent signaling, was also administered to Msh2wt mice as controls. Survival, lymphoma incidence and MSI tumor phenotype were investigated. Msh2+/- mice were found more tolerant than Msh2wt mice to the cytotoxicity of Aza. In Msh2+/- mice, Aza induced a high incidence of MSI lymphomas in a dose-dependent manner. In Msh2wt mice, a substantial lifespan was only observed at the lowest Aza dose. It was associated with the development of lymphomas, one of which displayed the MSI phenotype, unlike the CsA-induced lymphomas. Our findings define Aza as a risk factor for an MSI-driven lymphomagenesis process.


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