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Chronic Myeloproliferative Neoplasias

Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia

Leukemia volume 29, pages 869–876 (2015)Cite this article

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Abstract

Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single-nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

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Acknowledgements

This work was supported by the NIH Grants K08HL106576 (to STO), K12HL087107 (to STO), P01CA101937 (TJL), and T32HL007088 (to EKE, DACF). This research was also supported by a Sidney Kimmel Scholar Award, Leukemia Research Foundation New Investigator Award, Central Society for Clinical Research Early Career Development Award, Barnes-Jewish Hospital Foundation/Washington University Institute of Clinical and Translational Sciences Pilot Grant, and American Cancer Society Institutional Research Grant (all to STO). This work was supported by the Washington University Institute of Clinical and Translational Sciences Grant UL1TR000448 from the National Center for Advancing Translational Sciences of NIH. Technical support was provided by the Alvin J. Siteman Cancer Center Tissue Procurement and Flow Cytometry Cores, which are supported by NCI Cancer Center Support Grant P30CA91842. We thank D Link and J Xia for assistance with cell sorting and colony assays, K Martin, C Kaiwar and M Fulbright for performing JAK2 and U2AF1 genotyping experiments and J McMichael for assistance with illustrations.

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  1. E K Engle and D A C Fisher: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Washington University School of Medicine, St Louis, MO, USA

    E K Engle, D A C Fisher, D M Moore & S T Oh

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

    C A Miller, M D McLellan, R S Fulton & R K Wilson

  3. Division of Oncology, The Genome Institute, Washington University School of Medicine, St Louis, MO, USA

    T J Ley

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  1. E K Engle
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Engle, E., Fisher, D., Miller, C. et al. Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia. Leukemia 29, 869–876 (2015). https://doi.org/10.1038/leu.2014.289

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