Abstract

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4–15% of newly diagnosed childhood AML cases1,2,3. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A4,5,6. However, the etiology of 30–40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.

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Acknowledgements

We thank all the patients and their parents who allowed their leukemic samples to be stored and studied. We thank the Tissue Resources Laboratory, the Flow Cytometry and Cell Sorting Core, and the Clinical Applications of Core Technology Laboratories of the Hartwell Center for Bioinformatics and Biotechnology of St. Jude Children's Research Hospital. J.D.E.d.R. was funded by Stichting Kinderoncologisch Centrum Rotterdam (KOCR). A.O. and L.J.V. were funded by KIKA (Children Cancer-Free Foundation). M.F. was supported by the Dutch Cancer Society (KWF). F.L. was supported by the Italian Association for Research on Cancer (Associazione Italiana Ricerca sul Cancro; Special Grant “5xmille”-9962). This work was funded by the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project, the American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital, and the Eric Trump Foundation.

Author information

Author notes

    • Jasmijn D E de Rooij
    •  & Cristyn Branstetter

    These authors contributed equally to this work.

    • Franco Locatelli
    • , Dirk Reinhardt
    • , Marry M van den Heuvel-Eibrink
    • , C Michel Zwaan
    • , Maarten Fornerod
    •  & Tanja A Gruber

    These authors jointly supervised this work.

Affiliations

  1. Department of Pediatric Oncology, Erasmus MC–Sophia Children's Hospital, Rotterdam, the Netherlands.

    • Jasmijn D E de Rooij
    • , Askar Obulkasim
    • , Lonneke J Verboon
    • , Marry M van den Heuvel-Eibrink
    • , C Michel Zwaan
    •  & Maarten Fornerod
  2. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Cristyn Branstetter
    • , Jinjun Dang
    • , Cary Koss
    •  & Tanja A Gruber
  3. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Jing Ma
    • , Michael P Walsh
    • , Jinjun Cheng
    • , Guangchun Song
    • , James R Downing
    •  & Tanja A Gruber
  4. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Yongjin Li
    • , John Easton
    • , Heather L Mulder
    • , Pankaj Gupta
    • , Michael Edmonson
    • , Michael Rusch
    •  & Jinghui Zhang
  5. Department of Pediatric Hematology/Oncology, Medical School Hannover, Hannover, Germany.

    • Martin Zimmermann
  6. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Joshua Yew Suang Lim
    •  & Allen Eng Juh Yeoh
  7. Department of Pediatric Oncology, University of Duisburg-Essen, Essen, Germany.

    • Katarina Reinhardt
    •  & Dirk Reinhardt
  8. Department of Women's and Children's Health, University of Padova, Padova, Italy.

    • Martina Pigazzi
  9. Cancer Science Institute, National University of Singapore, Singapore.

    • Allen Eng Juh Yeoh
  10. Chang Gung Memorial Hospital–Linkou, Chang Gung University, Taoyuan City, Taiwan.

    • Lee-Yung Shih
  11. Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.

    • Der-Cherng Liang
  12. Section of Hematology, Department of Internal Medicine and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Stephanie Halene
  13. Department of Laboratory Medicine, Yale University, New Haven, Connecticut, USA.

    • Diane S Krause
  14. Department of Pediatric Hematology Oncology, University of Pavia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.

    • Franco Locatelli
  15. Department of Pediatric Oncology, Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.

    • Marry M van den Heuvel-Eibrink

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Contributions

T.A.G. and M.F. designed all experiments. J.C., H.L.M., and J.E. constructed libraries and sequenced samples. J.M. led the sequencing analysis. J.M., Y.L., M.P.W., M.R., G.S., A.O., M.F., M.E., P.G., and J.Z. performed computational data analyses. J.D.E.d.R., C.B., and L.J.V. performed validation experiments. C.B., J.M., and T.A.G. manually filtered SNV and indel calls on unpaired samples. C.K. and J.D. performed functional work on the HOX fusions. J.D.E.d.R., M.Z., and M.F. performed outcome analysis. J.Y.S.L., K.R., M.P., A.E.J.Y., L.-Y.S., D.-C.L., S.H., D.S.K., F.L., D.R., M.M.v.d.H.-E., C.M.Z., and T.A.G. provided annotated patient samples. J.D.E.d.R., C.B., J.R.D., F.L., D.R., M.M.v.d.H.-E., and C.M.Z. performed critical reading and contributed to the writing of the manuscript. M.F. and T.A.G. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Franco Locatelli or Dirk Reinhardt or Marry M van den Heuvel-Eibrink or C Michel Zwaan or Maarten Fornerod or Tanja A Gruber.

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DOI

https://doi.org/10.1038/ng.3772

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