title: High frequency of rare structural chromosome abnormalities at relapse of cytogenetically normal acute myeloid leukemia with FLT3 internal tandem duplication.
abstract: FLT3 internal tandem duplication (ITD) mutations are present in acute myeloid leukemia (AML) in 30% of patients with acute myeloid leukemia (AML), most commonly in those with a normal karyotype, and are associated with short relapse-free survival. Both in vitro and in vivo studies of FLT3-ITD cell lines have demonstrated reactive oxygen species-mediated DNA double-strand breaks and associated error-prone DNA repair as a mechanism of genomic instability, and we hypothesized that genomic instability might be manifested by cytogenetic changes at relapse of FLT3-ITD AML. We retrospectively reviewed charts of patients with cytogenetically normal (CN) FLT3-ITD AML treated at the University of Maryland Greenebaum Cancer Center, with attention to metaphase analysis results at relapse. Cytogenetic data were available from first and, when applicable, subsequent relapses for 15 patients diagnosed with CN FLT3-ITD AML. Among 12 patients with documented FLT3-ITD at first and, when applicable, subsequent relapse, 10 had cytogenetic changes, including nine with rare structural abnormalities. The high frequency of rare structural chromosome abnormalities at relapse in our case series supports a role of genomic instability in the genesis of relapse, and suggests that reactive oxygen species-generating and DNA repair pathways might be therapeutic targets in FLT3-ITD AML.
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, MD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Gourdin
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ning
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, MD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Ashkan
authors.initials: A
authors.lastname: Emadi
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, MD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Vu H
authors.initials: VH
authors.lastname: Duong
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, MD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Tidwell
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Ching
authors.initials: C
authors.lastname: Chen
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, MD; Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Feyruz V
authors.initials: FV
authors.lastname: Rassool
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, MD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD. Electronic address: mbaer@umm.edu.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
mesh_terms: D000328:Adult; D000368:Aged; D002869:Chromosome Aberrations; D020732:Cytogenetic Analysis; D004260:DNA Repair; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D017382:Reactive Oxygen Species; D012189:Retrospective Studies; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D017382:Reactive Oxygen Species; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia; FLT3-ITD; cytogenetics; genomic instability; relapse