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Acute Leukemias

The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia

Leukemia volume 28, pages 1242–1251 (2014)Cite this article

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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.

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Acknowledgements

Claudia Wiese kindly provided rad51d knockout CHO cells and wild-type human RAD51D construct. Jahangheer Shaik assisted with the copy number alteration permutation analysis. Todd Druley assisted with sequencing design. Gene chip analysis was performed at the Siteman Cancer Center Molecular Genomic Analysis Core Facility. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO, for the use of the Siteman Flow Cytometry Core, which provided the cell sorting service. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant no. P30 CA91842.This work was supported by NIH grants T32-HL007088 and K12 HL087107 (MAJ) and by the MDS Foundation, Washington University Siteman Cancer Center Research Development Award, and the Institute of Clinical and Translational Sciences UL1RR024992 (MJW). We thank Sharon Health for assistance with specimen banking and data management. We also thank Dr Dan Link, Dr Tim Ley and Dr Tom Ellenberger for helpful scientific discussions.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA

    M A Jacoby, R E De Jesus Pizarro, J Shao & M J Walter

  2. The Genome Institute, Washington University School of Medicine, St Louis, MO, USA

    D C Koboldt, R S Fulton & R K Wilson

  3. Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA

    G Zhou

  4. Department of Genetics, Washington University School of Medicine, St Louis, MO, USA

    R K Wilson & M J Walter

  5. Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA

    R K Wilson & M J Walter

  6. Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA

    R K Wilson

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Jacoby, M., De Jesus Pizarro, R., Shao, J. et al. The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia. Leukemia 28, 1242–1251 (2014). https://doi.org/10.1038/leu.2013.368

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