title: Mutation position within evolutionary subclonal architecture in AML.
abstract: Cytogenetic data suggest that acute myeloid leukemia (AML) develops through a process of branching evolution, especially during relapse and progression. Recent genomic data from AML cases using digital sequencing, temporal comparisons, xenograft cloning, and single-cell analysis indicate that most, if not all, AML cases emerge through branching evolution. According to a review of the current literature, the balanced translocations (t[15;17], t[8;21], and inv[16]) and nucleotide variants in DNMT3A and TET2 most commonly occur in the founding clone at diagnosis. These mutations are rarely gained or lost at relapse, and the latter 2 mutations are observed in elderly subjects with mosaic hematopoiesis antedating overt leukemia. In contrast, +8, +13, +22, -X, -Y, and nucleotide variants in FLT3, NRAS/KRAS, WT1, and KIT frequently occur in subclones and are observed either to emerge or to be lost at relapse. Because drugs that target mutations within a subclone are unlikely to eliminate all leukemic cells, it will be essential to understand not only which mutations a patient has but also how they organize within the leukemic subclonal architecture.
authors.affiliation: Washington University School of Medicine, Division of Oncology, Stem Cell Biology Section, St. Louis, MO. Electronic address: jwelch@dom.wustl.edu.
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
mesh_terms: D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D009711:Nucleotides / Q000235:genetics
chemical_list: D009711:Nucleotides