Abstract

Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML. Outside of signaling alterations, RUNX1-RUNX1T1 and CBFB-MYH11 AMLs demonstrated remarkably different spectra of cooperating mutations, as RUNX1-RUNX1T1 cases harbored recurrent mutations in DHX15 and ZBTB7A, as well as an enrichment of mutations in epigenetic regulators, including ASXL2 and the cohesin complex. This detailed analysis provides insights into the pathogenesis and development of CBF-AML, while highlighting dramatic differences in the landscapes of cooperating mutations for these related AML subtypes.

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Acknowledgements

We thank all the patients and their parents from the St. Jude Children's Research Hospital (USA) and the adult patients and their families from the German-Austrian AML Study Group (AMLSG). 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. 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 grants from the US National Institutes of Health (P30 CA021765 and K08 HL116605 (J.M.K.)). C.G.M. is a Pew Scholar in Biomedical Sciences and a St. Baldrick's Scholar. J.M.K. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. This study was supported in part by grants 01GI9981 and 01KG0605 from the German Bundesministerium für Bildung und Forschung (BMBF), grant 111911 from the Deutsche Krebshilfe and grant DO 704/3-1 from the Deutsche Forschungsgemeinschaft (DFG). K.D., H.D. and L.B. are supported by the Collaborative Research Center SFB 1074 funded by the DFG. L.B. is a Heisenberg Professor of the DFG (BU 1339/8-1).

Author information

Author notes

    • Anna K Andersson

    Present address: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.

    • Zachary J Faber
    • , Xiang Chen
    •  & Amanda Larson Gedman

    These authors contributed equally to this work.

Affiliations

  1. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Zachary J Faber
    • , Amanda Larson Gedman
    • , Jinjun Cheng
    • , Jing Ma
    • , Ina Radtke
    • , Jyh-Rong Chao
    • , Michael P Walsh
    • , Guangchun Song
    • , Anna K Andersson
    • , Jinjun Dang
    • , Li Dong
    • , Zhongling Cai
    • , Joy Nakitandwe
    • , Sheila Shurtleff
    • , Evan Parganas
    • , Charles G Mullighan
    • , Jeffery M Klco
    •  & James R Downing
  2. Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Xiang Chen
    • , Kristy Boggs
    • , Yu Liu
    • , Robert Huether
    • , Heather Mulder
    • , Gang Wu
    • , Michael Edmonson
    • , Michael Rusch
    • , Chunxu Qu
    • , Yongjin Li
    • , Bhavin Vadodaria
    • , Jianmin Wang
    • , Erin Hedlund
    • , Donald Yergeau
    • , John Easton
    •  & Jinghui Zhang
  3. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Xueyuan Cao
    •  & Stanley B Pounds
  4. McDonnell Genome Institute at Washington University, St. Louis, Missouri, USA.

    • Robert S Fulton
    • , Lucinda L Fulton
    • , Li Ding
    • , Elaine R Mardis
    •  & Richard K Wilson
  5. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Ching-Hon Pui
    • , Jeffrey E Rubnitz
    •  & Tanja A Gruber
  6. Department of Internal Medicine III, University of Ulm, Ulm, Germany.

    • Richard F Schlenk
    • , Peter Paschka
    • , Konstanze Döhner
    • , Hartmut Döhner
    •  & Lars Bullinger

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Contributions

Z.J.F., A.L.G., J.C., I.R., J.-R.C., A.K.A., J.D., L. Dong, Z.C., R.H. and E.P. contributed to the design of the study and conducted experiments. X. Chen, Y. Liu, G.S., J.M., M.P.W., G.W., M.E., M.R., C.Q., Y. Li, J.W., E.H., H.M., K.B., B.V., D.Y., J.N., J.E., S.S., R.S.F., L.L.F., L. Ding, E.R.M., R.K.W. and J.Z. contributed to the preparation and analysis of the sequencing data. X. Cao and S.B.P. provided statistical support. P.P., R.F.S., L.B., H.D., K.D., C.-H.P. and J.E.R. provided clinical samples and data. Z.J.F., A.L.G. and J.M.K. wrote the manuscript. R.K.W., T.A.G., C.G.M., L.B., J.Z., J.M.K. and J.R.D. contributed to study design and oversaw the study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lars Bullinger or Jinghui Zhang or Jeffery M Klco or James R Downing.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–24 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 1

    Clinicopathological information of 165 CBF-AML samples.

  2. 2.

    Supplementary Table 2

    Coding-region SNVs per case of CBF-AML.

  3. 3.

    Supplementary Table 3

    Coverage data for WGS cohort.

  4. 4.

    Supplementary Table 4

    Coverage data for WES cohort.

  5. 5.

    Supplementary Table 5

    Validated WGS sequence mutations for the 17 pediatric CBF-AML discovery cases.

  6. 6.

    Supplementary Table 6

    Validated whole-exome sequencing (WES) mutations for recurrency cohort.

  7. 7.

    Supplementary Table 7

    Recurrent somatic mutations in discovery and recurrency cohorts.

  8. 8.

    Supplementary Table 8

    Discovery cohort CNAs identified by WGS.

  9. 9.

    Supplementary Table 9

    Validated structural variants for the 17 pediatric CBF-AML discovery cases.

  10. 10.

    Supplementary Table 10

    Rank-ordered list of genes differentially expressed in DHX15 knockdown cells and their enrichment in the Reactome mRNA splicing gene set.

  11. 11.

    Supplementary Table 11

    Rank-ordered list of genes differentially expressed in DHX15 knockdown cells and their enrichment in the KEGG ribosome gene set.

  12. 12.

    Supplementary Table 12

    GSEA results after DHX15 knockdown.

  13. 13.

    Supplementary Table 13

    Spectral counts (SCs) of proteins identified in pulldown experiments with wild-type (Wt) or R222G (Mut) DHX15.

  14. 14.

    Supplementary Table 14

    RNA–seq RUNX1-RUNX1T1 upregulated genes.

  15. 15.

    Supplementary Table 15

    RNA–seq RUNX1-RUNX1T1 downregulated genes.

  16. 16.

    Supplementary Table 16

    GSEA gene list.

  17. 17.

    Supplementary Table 17

    Copy number analysis of de novo–relapse pair.

  18. 18.

    Supplementary Table 18

    Deep sequencing read counts in diagnosis, germline and relapse trios.

  19. 19.

    Supplementary Table 19

    Oligonucleotides used in this study.

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https://doi.org/10.1038/ng.3709

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