The Origin and Evolution of Mutations in Acute Myeloid Leukemia

John S Welch; Michael H Tomasson; Timothy J Ley; Daniel C Link; Christopher A Miller; David E Larson; Daniel C Koboldt; Lukas D Wartman; Tamara L Lamprecht; Fulu Liu; Jun Xia; Cyriac Kandoth; Robert S Fulton; Michael D McLellan; David J Dooling; John W Wallis; Ken Chen; Christopher C Harris; Heather K Schmidt; Joelle M Kalicki-Veizer; Charles Lu; Qunyuan Zhang; Ling Lin; Michelle D O’Laughlin; Joshua F McMichael; Kim D Delehaunty; Lucinda A Fulton; Vincent J Magrini; Sean D McGrath; Ryan T Demeter; Tammi L Vickery; Jasreet Hundal; Lisa L Cook; Gary W Swift; Jerry P Reed; Patricia A Alldredge; Todd N Wylie; Jason R Walker; Mark A Watson; Sharon E Heath; William D Shannon; Nobish Varghese; Rakesh Nagarajan; Jacqueline E Payton; Jack D Baty; Shashikant Kulkarni; Jeffery M Klco; Peter Westervelt; Matthew J Walter; Timothy A Graubert; John F DiPersio; Li Ding; Elaine R Mardis; Richard K Wilson

doi:10.1016/j.cell.2012.06.023

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The Origin and Evolution of Mutations in Acute Myeloid Leukemia

Journal article

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The Origin and Evolution of Mutations in Acute Myeloid Leukemia

John S Welch, Michael H Tomasson, Timothy J Ley, Daniel C Link, Christopher A Miller, David E Larson, Daniel C Koboldt, Lukas D Wartman, Tamara L Lamprecht, Fulu Liu, …

Cell, Vol.150(2), pp.264-278

07/20/2012

DOI: 10.1016/j.cell.2012.06.023

PMCID: PMC3407563

PMID: 22817890

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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. [Display omitted] ► Normal HSPCs contain random background mutations that increase with aging ► AML genomes contain hundreds of mutations, but very few are recurrent ► Comparison of M1 and M3 AML genomes identifies initiating versus cooperating mutations ► Most AML mutations are probably background events in HSPCs, “captured” by cloning Comparison of the genomes of two groups of patients, each with a different form of AML, allows the resolution of potential driver and cooperating mutations in each disease and reveals that the genetic history of all AML cases is marked by random, benign mutations acquired by normal HSPCs as a function of age.

Details

Title: Subtitle: The Origin and Evolution of Mutations in Acute Myeloid Leukemia
Creators: John S Welch - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Michael H Tomasson - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Timothy J Ley - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Daniel C Link - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Christopher A Miller - The Genome Institute, Washington University, St. Louis, MO 63110, USA
David E Larson - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Daniel C Koboldt - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Lukas D Wartman - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Tamara L Lamprecht - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Fulu Liu - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Jun Xia - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Cyriac Kandoth - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Robert S Fulton - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Michael D McLellan - The Genome Institute, Washington University, St. Louis, MO 63110, USA
David J Dooling - The Genome Institute, Washington University, St. Louis, MO 63110, USA
John W Wallis - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Ken Chen - Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
Christopher C Harris - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Heather K Schmidt - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Joelle M Kalicki-Veizer - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Charles Lu - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Qunyuan Zhang - Department of Genetics, Washington University, St. Louis, MO 63110, USA
Ling Lin - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Michelle D O’Laughlin - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Joshua F McMichael - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Kim D Delehaunty - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Lucinda A Fulton - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Vincent J Magrini - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Sean D McGrath - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Ryan T Demeter - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Tammi L Vickery - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Jasreet Hundal - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Lisa L Cook - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Gary W Swift - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Jerry P Reed - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Patricia A Alldredge - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Todd N Wylie - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Jason R Walker - The Genome Institute, Washington University, St. Louis, MO 63110, USA
Mark A Watson - Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA
Sharon E Heath - Department of Medicine, Washington University, St. Louis, MO 63110, USA
William D Shannon - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Nobish Varghese - Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA
Rakesh Nagarajan - Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA
Jacqueline E Payton - Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA
Jack D Baty - Division of Biostatistics, Washington University, St. Louis, MO 63110, USA
Shashikant Kulkarni - Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA
Jeffery M Klco - Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA
Peter Westervelt - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Matthew J Walter - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Timothy A Graubert - Department of Medicine, Washington University, St. Louis, MO 63110, USA
John F DiPersio - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Li Ding - Department of Medicine, Washington University, St. Louis, MO 63110, USA
Elaine R Mardis - Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA
Richard K Wilson - Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA
Resource Type: Journal article
Publication Details: Cell, Vol.150(2), pp.264-278
Publisher: Elsevier Inc
DOI: 10.1016/j.cell.2012.06.023
PMID: 22817890
PMCID: PMC3407563
ISSN: 0092-8674
eISSN: 1097-4172
Language: English
Date published: 07/20/2012
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094212402771

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