Bodo Sahra, Svrcek Magali, Sourrouille Isabelle, Cuillières-Dartigues Peggy, Ledent Tatiana, Dumont Sylvie, Dinard Laetitia, Lafitte Philippe, Capel Camille, Collura Ada, Buhard Olivier, Wanherdrick Kristell, Chalastanis Alexandra, Penard-Lacronique Virginie, Fabiani Bettina, Fléjou Jean-François, Brousse Nicole, Beaugerie Laurent, Duval Alex, Muleris Martine
INSERM, 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.
Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Oncotarget. 2015 Sep 22;6(28):24969-77. doi: 10.18632/oncotarget.4638.
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 Msh2(wt) mice as controls. Survival, lymphoma incidence and MSI tumor phenotype were investigated. Msh2(+/-) mice were found more tolerant than Msh2(wt) mice to the cytotoxicity of Aza. In Msh2(+/-) mice, Aza induced a high incidence of MSI lymphomas in a dose-dependent manner. In Msh2(wt) 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.
错配修复（MMR）缺陷细胞在体外对硫嘌呤的耐受性增强，因为它们能逃避由药物诱导的DNA损伤的MMR依赖性信号传导所导致的细胞凋亡。长期使用包括硫嘌呤前药硫唑嘌呤（Aza）在内的免疫抑制剂被认为是发生迟发性白血病/淋巴瘤的一个风险因素，这些白血病/淋巴瘤表现出微卫星不稳定性（MSI）表型，这是MMR系统缺陷的标志。我们在小鼠中进行了一项剂量效应研究，以调查与长期Aza治疗相关的MSI淋巴瘤的发生情况。在两年多的时间里，将Aza给予MMR基因Msh2野生型、缺失型或杂合型的小鼠。还将具有不依赖MMR信号传导的免疫抑制剂环孢素A给予Msh2（野生型）小鼠作为对照。研究了生存率、淋巴瘤发病率和MSI肿瘤表型。发现Msh2（+/-）小鼠比Msh2（野生型）小鼠对Aza的细胞毒性更耐受。在Msh2（+/-）小鼠中，Aza以剂量依赖性方式诱导了高发病率的MSI淋巴瘤。在Msh2（野生型）小鼠中，仅在最低Aza剂量下观察到显著的寿命延长。这与淋巴瘤的发生有关，其中一个淋巴瘤表现出MSI表型，这与环孢素A诱导的淋巴瘤不同。我们的研究结果将Aza定义为MSI驱动的淋巴瘤发生过程的一个风险因素。
