title: 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.
authors: Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors: John S
authors: JS
authors: Welch
authors: Timothy J
authors: TJ
authors: Ley
authors: Daniel C
authors: DC
authors: Link
authors: Christopher A
authors: CA
authors: Miller
authors: David E
authors: DE
authors: Larson
authors: Daniel C
authors: DC
authors: Koboldt
authors: Lukas D
authors: LD
authors: Wartman
authors: Tamara L
authors: TL
authors: Lamprecht
authors: Fulu
authors: F
authors: Liu
authors: Jun
authors: J
authors: Xia
authors: Cyriac
authors: C
authors: Kandoth
authors: Robert S
authors: RS
authors: Fulton
authors: Michael D
authors: MD
authors: McLellan
authors: David J
authors: DJ
authors: Dooling
authors: John W
authors: JW
authors: Wallis
authors: Ken
authors: K
authors: Chen
authors: Christopher C
authors: CC
authors: Harris
authors: Heather K
authors: HK
authors: Schmidt
authors: Joelle M
authors: JM
authors: Kalicki-Veizer
authors: Charles
authors: C
authors: Lu
authors: Qunyuan
authors: Q
authors: Zhang
authors: Ling
authors: L
authors: Lin
authors: Michelle D
authors: MD
authors: O'Laughlin
authors: Joshua F
authors: JF
authors: McMichael
authors: Kim D
authors: KD
authors: Delehaunty
authors: Lucinda A
authors: LA
authors: Fulton
authors: Vincent J
authors: VJ
authors: Magrini
authors: Sean D
authors: SD
authors: McGrath
authors: Ryan T
authors: RT
authors: Demeter
authors: Tammi L
authors: TL
authors: Vickery
authors: Jasreet
authors: J
authors: Hundal
authors: Lisa L
authors: LL
authors: Cook
authors: Gary W
authors: GW
authors: Swift
authors: Jerry P
authors: JP
authors: Reed
authors: Patricia A
authors: PA
authors: Alldredge
authors: Todd N
authors: TN
authors: Wylie
authors: Jason R
authors: JR
authors: Walker
authors: Mark A
authors: MA
authors: Watson
authors: Sharon E
authors: SE
authors: Heath
authors: William D
authors: WD
authors: Shannon
authors: Nobish
authors: N
authors: Varghese
authors: Rakesh
authors: R
authors: Nagarajan
authors: Jacqueline E
authors: JE
authors: Payton
authors: Jack D
authors: JD
authors: Baty
authors: Shashikant
authors: S
authors: Kulkarni
authors: Jeffery M
authors: JM
authors: Klco
authors: Michael H
authors: MH
authors: Tomasson
authors: Peter
authors: P
authors: Westervelt
authors: Matthew J
authors: MJ
authors: Walter
authors: Timothy A
authors: TA
authors: Graubert
authors: John F
authors: JF
authors: DiPersio
authors: Li
authors: L
authors: Ding
authors: Elaine R
authors: ER
authors: Mardis
authors: Richard K
authors: RK
authors: Wilson
mesh_terms: D000328:Adult; D000368:Aged; D060965:Clonal Evolution; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D055106:Genome-Wide Association Study; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D012008:Recurrence; D012867:Skin / Q000378:metabolism; D055815:Young Adult
chemical_list: D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein