Journal Article

Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia

Heath, Sharon, Mardis, Elaine R., Graubert, Timothy A., Link, Daniel C., Miller, Christopher A., Wilson, Richard K., Lamprecht, Tamara L., Welch, John S., Walter, Matthew J., Shen, Dong, Young, Andrew L., Hundal, Jasreet, Klco, Jeffery M., DiPersio, John F., Westervelt, Peter, Ley, Timothy J., Wong, Terrence N., Ramsingh, Giridharan, Fulton, Robert S., Ding, Li, Druley, Todd E., Touma, Waseem, Baty, Jack D.

2015

Overview

Somatic TP53 mutations are highly prevalent in therapy-related acute myeloid leukaemia and myelodysplastic syndrome, which arise as complications of cytotoxic chemotherapy or radiotherapy; although it was believed that these TP53 mutations are directly induced by cytotoxic therapy, new data indicate that they predate cytotoxic therapy and that haematopoietic progenitors harbouring these pre-existing mutations may selectively expand after exposure to chemotherapy or radiotherapy. TP53 mutations predate cytotoxic therapy The clonal haematopoietic disorders known as therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) typically develop 1 to 5 years after exposure to chemotherapy or radiotherapy. TP53 mutations are selectively enriched in t-AML/t-MDS, and were thought to be directly induced by cytotoxic therapy. Now Daniel Link and colleagues present genome sequencing data that suggest the TP53 mutations predate cytotoxic therapy. It appears that rare haematopoietic stem/progenitor cells in blood or bone marrow carry age-related TP53 mutations, and that these cells undergo clonal expansion only after selective pressure applied by chemotherapy. 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 de novo 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 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 45/23 / 45/77 / 631/208/514/2254 / 631/67/1990/283/1897 / 64/60 / Alleles / Animals / Bone marrow / Cancer / Cell Lineage - drug effects / Cell Lineage - genetics / Cell Proliferation / Chemotherapy / Chromosomes / Clone Cells / Cytogenetics / Cytotoxicity / DNA Damage / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Ethylnitrosourea - pharmacology / Evolution, Molecular / Gene mutations / Genes / Genes, p53 - genetics / Genomes / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - drug effects / Hematopoietic Stem Cells - metabolism / Hematopoietic Stem Cells - pathology / Heterozygote / Humanities and Social Sciences / Humans / letter / Leukemia / Leukemia, Myeloid, Acute - chemically induced / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Medical research / Medicine, Experimental / Mice / Models, Genetic / multidisciplinary / Mutation / Mutation - drug effects / Mutation - genetics / Myelocytic leukemia / Nonlymphoid leukemia / Radiotherapy / Risk factors / Science