1. Role of TP53 mutations in the origin and evolution of therapy--related acute myeloid leukaemia
- Author
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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 E., Link, Daniel C., and Wilson, Richard K.
- Subjects
Gene mutations -- Health aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy (1). There are several features that distinguish t-AML from denovo AML, including a higher incidence of TP53 mutations (2,3), abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy (4). 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 denovo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. W e 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/tMDS, 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.sup.+/-] haematopoietic stem/progenitor cells (HSPCs), the [Tp53.sup.+/-] 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., t-AML and t-MDS are clonal haematopoietic disorders that typically develop 1-5 years after exposure to chemotherapy or radiotherapy (1). To understand better how prior cytotoxic therapy contributes to the high [...]
- Published
- 2015