Wong Terrence N, Ramsingh Giridharan, Young Andrew L, Miller Christopher A, Touma Waseem, Welch John S, Lamprecht Tamara L, Shen Dong, Hundal Jasreet, Fulton Robert S, Heath Sharon, Baty Jack D, Klco Jeffery M, Ding Li, Mardis Elaine R, Westervelt Peter, DiPersio John F, Walter Matthew J, Graubert Timothy A, Ley Timothy J, Druley Todd, Link Daniel C, Wilson Richard K
Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.
Department of Medicine, Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, CA.
Nature. 2015 Feb 26;518(7540):552-555. doi: 10.1038/nature13968. Epub 2014 Dec 8.
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.
治疗相关急性髓系白血病（t-AML）和治疗相关骨髓增生异常综合征（t-MDS）是细胞毒性化疗和/或放疗公认的并发症。t-AML与原发性AML有几个不同特征，包括TP53突变发生率较高、5号或7号染色体异常、复杂细胞遗传学以及对化疗反应降低。然而，尚不清楚先前接触细胞毒性治疗如何影响白血病发生。特别是，TP53突变在t-AML/t-MDS中选择性富集的机制尚不清楚。在此，通过对22例t-AML患者的基因组进行测序，我们发现t-AML和原发性AML中体细胞单核苷酸变异总数以及化疗相关颠换百分比相似，表明先前化疗不会诱导全基因组DNA损伤。我们鉴定出4例t-AML/t-MDS，其中诊断时发现的精确TP53突变在t-AML/t-MDS发生前3至6年的动员血白细胞或骨髓中也以低频率（0.003 - 0.7%）存在，包括2例在任何化疗之前就检测到相关TP53突变的病例。此外，在未接受化疗的健康老年个体的小部分外周血细胞中鉴定出功能性TP53突变。最后，在含有野生型和Tp53(+/-)造血干/祖细胞（HSPCs）的小鼠骨髓嵌合体中，Tp53(+/-) HSPCs在接触化疗后优先扩增。这些数据表明细胞毒性治疗不会直接诱导TP53突变。相反，它们支持一种模型，即携带与年龄相关TP53突变的罕见HSPCs对化疗有抗性并在治疗后优先扩增。在起始HSPC克隆中早期获得TP53突变可能导致t-AML/t-MDS患者典型的频繁细胞遗传学异常和对化疗反应不佳。
