Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation
Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation
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DOI：
10.1182/blood-2003-11-3938
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发表时间：
2004-08-01
期刊：
影响因子：
20.3
通讯作者：
Karran, P
中科院分区：
文献类型：
--
作者：
Offman, J;Opelz, G;Karran, P
器官移植后的免疫抑制是公认的皮肤癌和淋巴瘤的危险因素。我们研究了移植后患者中是否也有过多的白血病，以及这是否可能与特定的免疫抑制治疗有关。来自17万多例患者的数据表明，器官移植与急性髓性白血病（AML）的风险显著增加相关。AML在心脏移植和肺移植后比肾移植后更常见，并且与硫嘌呤（一种硫嘌呤前药）的免疫抑制有关。细胞对硫嘌呤的抗性与DNA错配修复（MMR）缺陷有关。我们证明，硫嘌呤治疗人类细胞在体外选择变异有缺陷的MMR。与患者骨髓的类似选择一致，在7例患者中，7例与移植相关的AML/骨髓增生异常综合征（MDS）表现出微卫星不稳定性（MSI），这是MMR缺陷的诊断。由于MSI在新发AML中很少发生，我们得出结论，mmr缺陷、硫唑嘌呤耐药骨髓细胞的选择性增殖可能对接受器官移植的患者的AML/MDS的发展起重要作用。确定硫唑嘌呤是AML/MDS的一个危险因素，表明停止使用硫唑嘌呤作为免疫抑制剂可能会降低移植后AML/MDS的发病率。
Immunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplant-related AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selective proliferation of MMR-defective, azathioprine-resistant myeloid cells may contribute significantly to the development of AML/MDS in patients who have received organ transplants. Identifying azathioprine as a risk factor for AML/MDS suggests that discontinuing the use of azathioprine as an immunosuppressant might reduce the incidence of posttransplantation AML/MDS.