title: The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia.
abstract: The complex chromosomal aberrations found in therapy-related acute myeloid leukemia (t-AML) suggest that the DNA double-strand break (DSB) response may be altered. In this study we examined the DNA DSB response of primary bone marrow cells from t-AML patients and performed next-generation sequencing of 37 canonical homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA repair genes, and a subset of DNA damage response genes using tumor and paired normal DNA obtained from t-AML patients. Our results suggest that the majority of t-AML patients (11 of 15) have tumor-cell intrinsic, functional dysregulation of their DSB response. Distinct patterns of abnormal DNA damage response in myeloblasts correlated with acquired genetic alterations in TP53 and the presence of inferred chromothripsis. Furthermore, the presence of trisomy 8 in tumor cells was associated with persistently elevated levels of DSBs. Although tumor-acquired point mutations or small indels in canonical HR and NHEJ genes do not appear to be a dominant means by which t-AML leukemogenesis occurs, our functional studies suggest that an abnormal response to DNA damage is a common finding in t-AML.
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Jacoby
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: De Jesus Pizarro
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shao
authors.affiliation: The Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Koboldt
authors.affiliation: The Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.affiliation: 1] The Genome Institute, Washington University School of Medicine, St Louis, MO, USA [2] Department of Genetics, Washington University School of Medicine, St Louis, MO, USA [3] Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA [4] Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: 1] Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA [2] Department of Genetics, Washington University School of Medicine, St Louis, MO, USA [3] Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M J
authors.identifier: 0000000277531091
authors.initials: MJ
authors.lastname: Walter
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D001853:Bone Marrow / Q000473:pathology*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D020552:Comet Assay; D055028:Comparative Genomic Hybridization; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D042381:Granulocyte Precursor Cells / Q000473:pathology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C468783:H2AX protein, human; D006657:Histones; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53