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Somatic mutational landscape of AML with inv(16) or t(8;21) identifies patterns of clonal evolution in relapse leukemia

Leukemia volume 30, pages 501–504 (2016)Cite this article

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Acute myeloid leukemia (AML) with chromosomal rearrangements inv(16)(p13q22) or t(16;16)(p13;q22) (collectively referred to as inv(16)) and t(8;21)(q22;q22) are classified as core binding factor (CBF) AML, which accounts for ~20% of all AML cases.1 The resulting oncogenic fusion genes, CBFB–MYH11 and RUNX1–RUNX1T1, respectively, involve members of the CBF family of transcription factors, RUNX1 and its binding partner CBFβ.1 Overall, patients with CBF AML have a favorable prognosis compared with other AML cytogenetic groups, with the majority of them (>85%) achieving complete remission (CR) with cytarabine/anthracycline-based regimens.2 However, approximately half of the CBF AML patients relapse, with a median time to relapse of 2.5 years after achieving CR2 and the overall survival at 5 years of only 51%.3 Thus, it is imperative to develop novel and ‘personalized’ treatments for these patients. However, the mechanisms leading to relapse remain elusive. The goal of our study was to elucidate the mechanisms of relapse in CBF AML by unbiased genomic approaches. Therefore, we applied whole-exome sequencing (WES) and single-nucleotide polymorphism (SNP) arrays to analyze the somatic mutational landscape of matched diagnosis and relapse DNA samples from CBF AML patients. Here we report our data on the identification of putative novel AML driver genes and mechanisms of relapse.

WES and SNP arrays were performed on diagnosis, CR and relapse samples from 10 patients and diagnosis and relapse samples from additional three patients on the CALGB 8461 protocol.4 Patient details and study design are described in Supplementary methods, Supplementary Table S1 and Supplementary Figure S1. DNA from CR samples was used as the germline control to identify somatic single-nucleotide variants (SNVs) and copy-number variants (CNVs). We obtained high quality WES reads with average breadth of coverage of 90.5% of exome (range: 85–93%) and average depth of coverage of 82.4 × (range: 39.3–108.4 × ; Supplementary Table S2).

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Acknowledgements

We thank Ms Julia Fekecs for her help with illustrations and Ms Ursula Harper for performing DNA matching using a panel of polymorphic markers randomly distributed throughout the genome. Supported by the Intramural Research Program of National Human Genome Research Institute, NIH; CA101140, CA16058, CA140158, CA180861 and the Leukemia Clinical Research Foundation.

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Authors and Affiliations

  1. Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    R Sood & P Liu

  2. Zebrafish Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    R Sood & B Carrington

  3. Comparative Genomics Analysis Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    N F Hansen & J C Mullikin

  4. Genomics Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    F X Donovan & S C Chandrasekharappa

  5. Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA

    D Bucci, J Kohlschmidt, M A Caligiuri, G Marcucci & C D Bloomfield

  6. NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    B Maskeri, A Young & J C Mullikin

  7. Bioinformatics and Scientific Programming Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    N S Trivedi

  8. Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

    J Kohlschmidt

  9. Medical Oncology/Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA

    R M Stone

  10. Cancer Genomics Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    S C Chandrasekharappa

  11. Department of Hematology and Hematopoietic Cell Transplantation, Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, CA, USA

    G Marcucci

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  1. R Sood
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Correspondence to P Liu.

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Sood, R., Hansen, N., Donovan, F. et al. Somatic mutational landscape of AML with inv(16) or t(8;21) identifies patterns of clonal evolution in relapse leukemia. Leukemia 30, 501–504 (2016). https://doi.org/10.1038/leu.2015.141

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