title: Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.
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. 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.
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.
authors.forename: Terrence N
authors.initials: TN
authors.lastname: Wong
authors.affiliation: Department of Medicine, Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, CA.
authors.forename: Giridharan
authors.initials: G
authors.lastname: Ramsingh
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Young
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, MO.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.
authors.forename: Waseem
authors.initials: W
authors.lastname: Touma
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lamprecht
authors.affiliation: Astra Zeneca, Gaithersburg, MD.
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, MO.
authors.forename: Jasreet
authors.initials: J
authors.lastname: Hundal
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, MO.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.
authors.forename: Sharon
authors.initials: S
authors.lastname: Heath
authors.affiliation: Division of Biostatistics, Washington University, St. Louis, MO.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Baty
authors.affiliation: Department of Pathology and Immunology, Washington University, St Louis, MO.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Klco
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.|Department of Genetics, Washington University, St. Louis, MO.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Todd
authors.initials: T
authors.lastname: Druley
authors.affiliation: Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, MO.|Siteman Cancer Center, Washington University, St. Louis, MO.|Department of Genetics, Washington University, St. Louis, MO.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
mesh_terms: D000483:Alleles; D000818:Animals; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation; D002999:Clone Cells; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005038:Ethylnitrosourea / Q000494:pharmacology; D019143:Evolution, Molecular; D016158:Genes, p53 / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008957:Models, Genetic; D009154:Mutation / Q000187:drug effects / Q000235:genetics*
chemical_list: D005038:Ethylnitrosourea