Publication Date:
2014-12-10
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403236/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403236/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- Wilson, Richard K -- K08 HL116605/HL/NHLBI NIH HHS/ -- P01 CA101937/CA/NCI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Feb 26;518(7540):552-5. doi: 10.1038/nature13968. Epub 2014 Dec 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA. ; Department of Medicine, Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, California 90089, USA. ; Department of Pediatrics, Division of Hematology/Oncology, Washington University, St Louis, Missouri 63110, USA. ; The Genome Institute, Washington University, St Louis, Missouri 63110, USA. ; 1] Department of Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA [2] Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA. ; AstraZeneca, Gaithersburg, Maryland 20878, USA. ; Division of Biostatistics, Washington University, St Louis, Missouri 63110, USA. ; Department of Pathology and Immunology, Washington University, St Louis, Missouri 63110, USA. ; 1] The Genome Institute, Washington University, St Louis, Missouri 63110, USA [2] Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA [3] Department of Genetics, Washington University, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25487151" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Animals
;
Cell Lineage/drug effects/*genetics
;
Cell Proliferation
;
Clone Cells
;
DNA Damage
;
Drug Resistance, Neoplasm/drug effects/genetics
;
Ethylnitrosourea/pharmacology
;
Evolution, Molecular
;
Genes, p53/*genetics
;
Hematopoietic Stem Cells/cytology/drug effects/metabolism/pathology
;
Heterozygote
;
Humans
;
Leukemia, Myeloid, Acute/*chemically induced/*genetics/pathology
;
Mice
;
Models, Genetic
;
Mutation/drug effects/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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