title: Clonal architecture of secondary acute myeloid leukemia.
abstract: BACKGROUND
  The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood.
  
  
  METHODS
  We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations.
  
  
  RESULTS
  Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene.
  
  
  CONCLUSIONS
  Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.).
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Jin
authors.initials: J
authors.lastname: Shao
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.forename: David E
authors.initials: DE
authors.lastname: Larson
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.forename: David
authors.initials: D
authors.lastname: Dooling
authors.forename: Rachel
authors.initials: R
authors.lastname: Abbott
authors.forename: Robert
authors.initials: R
authors.lastname: Fulton
authors.forename: Vincent
authors.initials: V
authors.lastname: Magrini
authors.forename: Heather
authors.initials: H
authors.lastname: Schmidt
authors.forename: Joelle
authors.initials: J
authors.lastname: Kalicki-Veizer
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Laughlin
authors.forename: Xian
authors.initials: X
authors.lastname: Fan
authors.forename: Marcus
authors.initials: M
authors.lastname: Grillot
authors.forename: Sarah
authors.initials: S
authors.lastname: Witowski
authors.forename: Sharon
authors.initials: S
authors.lastname: Heath
authors.forename: John L
authors.initials: JL
authors.lastname: Frater
authors.forename: William
authors.initials: W
authors.lastname: Eades
authors.forename: Michael
authors.initials: M
authors.lastname: Tomasson
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
mesh_terms: D000293:Adolescent; D000328:Adult; D001854:Bone Marrow Cells / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002999:Clone Cells; D015894:Genome, Human; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012867:Skin; D055815:Young Adult