Dataset Information

The origin and evolution of mutations in acute myeloid leukemia.

ABSTRACT: Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is "captured" as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.

SUBMITTER: Welch JS

PROVIDER: S-EPMC3407563 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Publications

The origin and evolution of mutations in acute myeloid leukemia.

Welch John S JS Ley Timothy J TJ Link Daniel C DC Miller Christopher A CA Larson David E DE Koboldt Daniel C DC Wartman Lukas D LD Lamprecht Tamara L TL Liu Fulu F Xia Jun J Kandoth Cyriac C Fulton Robert S RS McLellan Michael D MD Dooling David J DJ Wallis John W JW Chen Ken K Harris Christopher C CC Schmidt Heather K HK Kalicki-Veizer Joelle M JM Lu Charles C Zhang Qunyuan Q Lin Ling L O'Laughlin Michelle D MD McMichael Joshua F JF Delehaunty Kim D KD Fulton Lucinda A LA Magrini Vincent J VJ McGrath Sean D SD Demeter Ryan T RT Vickery Tammi L TL Hundal Jasreet J Cook Lisa L LL Swift Gary W GW Reed Jerry P JP Alldredge Patricia A PA Wylie Todd N TN Walker Jason R JR Watson Mark A MA Heath Sharon E SE Shannon William D WD Varghese Nobish N Nagarajan Rakesh R Payton Jacqueline E JE Baty Jack D JD Kulkarni Shashikant S Klco Jeffery M JM Tomasson Michael H MH Westervelt Peter P Walter Matthew J MJ Graubert Timothy A TA DiPersio John F JF Ding Li L Mardis Elaine R ER Wilson Richard K RK

Cell 20120701 2

Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells ( ...[more]

PMID: 22817890

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Project 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.

Dataset Information

The origin and evolution of mutations in acute myeloid leukemia.

Publications

The origin and evolution of mutations in acute myeloid leukemia.

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