Department of Internal Medicine, Division of Haematology, Medical University of Graz, Graz, Austria.
Br J Pharmacol. 2011 Feb;162(4):792-805. doi: 10.1111/j.1476-5381.2010.01100.x.
Therapy-related myeloid neoplasms (t-MNs) are serious long-term consequences of cytotoxic treatments for an antecedent disorder. t-MNs are observed after ionizing radiation as well as conventional chemotherapy including alkylating agents, topoisomerase-II-inhibitors and antimetabolites. In addition, adjuvant use of recombinant human granulocyte-colony stimulating factor may also increase the risk of t-MNs. There is clinical and biological overlap between t-MNs and high-risk de novo myelodysplastic syndromes and acute myeloid leukaemia suggesting similar mechanisms of leukaemogenesis. Human studies and animal models point to a prominent role of genetic susceptibilty in the pathogenesis of t-MNs. Common genetic variants have been identified that modulate t-MN risk, and t-MNs have been observed in some cancer predisposition syndromes. In either case, establishing a leukaemic phenotype requires acquisition of somatic mutations - most likely induced by the cytotoxic treatment. Knowledge of the specific nature of the initiating exposure has allowed the identification of crucial pathogenetic mechanisms and for these to be modelled in vitro and in vivo. Prognosis of patients with t-MNs is dismal and at present, the only curative approach for the majority of these individuals is haematopoietic stem cell transplantation, which is characterized by high transplant-related mortality rates. Novel transplantation strategies using reduced intensity conditioning regimens as well as novel drugs - demethylating agents and targeted therapies - await clinical testing and may improve outcome. Ultimately, individual assessment of genetic risk factors may translate into tailored therapies and establish a strategy for reducing t-MN incidences without jeopardizing therapeutic success rates for the primary disorders.
治疗相关髓系肿瘤（t-MNs）是先前疾病的细胞毒性治疗的严重长期后果。t-MNs 可见于电离辐射以及常规化疗后，包括烷化剂、拓扑异构酶-II 抑制剂和抗代谢物。此外，重组人粒细胞集落刺激因子的辅助使用也可能增加 t-MNs 的风险。t-MNs 与高危新发骨髓增生异常综合征和急性髓系白血病之间存在临床和生物学重叠，提示白血病发生机制相似。人体研究和动物模型表明遗传易感性在 t-MNs 的发病机制中起重要作用。已经确定了一些常见的遗传变异可以调节 t-MN 的风险，并且在一些癌症易感性综合征中也观察到了 t-MNs。在任何一种情况下，建立白血病表型都需要获得体细胞突变——这些突变很可能是由细胞毒性治疗诱导的。对起始暴露的特定性质的了解使得能够确定关键的发病机制，并在体外和体内对这些机制进行建模。t-MNs 患者的预后不佳，目前，这些患者中的大多数的唯一治愈方法是造血干细胞移植，这种方法的移植相关死亡率很高。使用低强度预处理方案和新型药物（去甲基化剂和靶向治疗）的新型移植策略正在等待临床测试，可能会改善预后。最终，对遗传风险因素的个体评估可能转化为量身定制的治疗方法，并建立一种降低 t-MN 发生率而不危及主要疾病治疗成功率的策略。
