title: Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia.
abstract: The frequent occurrence of persistent or relapsed disease after induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we used SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients who achieved complete remission with chemotherapy and subsequently relapsed and 11 sample pairs from patients with persistent disease after induction chemotherapy. Through review of aCNA/cnLOH and gene mutation profiles in informative cases, we demonstrate that relapsed AML invariably represents re-emergence or evolution of a founder clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered cases with 2 coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant, respectively. These data support the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Parkin
authors.forename: Peter
authors.initials: P
authors.lastname: Ouillette
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Li
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keller
authors.forename: Cindy
authors.initials: C
authors.lastname: Lam
authors.forename: Diane
authors.initials: D
authors.lastname: Roulston
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Kerby
authors.initials: K
authors.lastname: Shedden
authors.forename: Sami N
authors.initials: SN
authors.lastname: Malek
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D060965:Clonal Evolution / Q000235:genetics*; D002999:Clone Cells; D055028:Comparative Genomic Hybridization; D005434:Flow Cytometry; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents