Abstract

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32–39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

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Acknowledgements

We thank J. Morris, E. Walker and A. Merriman for performing SNP and gene expression microarrays and G. Zambetti and P. Brindle for insightful discussions of TP53 and CREBBP mutational data, respectively. We also thank H. Mulder, R. Collins, M. Barbato, E. Stonerock, E. Pinto and M. Ellis for technical assistance, the Tissue Resources Core facility and the Flow Cytometry and Cell Sorting Core facility of the St. Jude Children's Research Hospital (SJCRH). This work was supported by The Henry Schueler 41&9 Foundation in conjunction with Partnership for Cures, the St. Baldrick's Foundation, US National Cancer Institute (NCI) grant RC4CA156329, US National Institutes of Health (NIH) grants CA21765 and U01 GM92666, the American Association for Cancer Research (AACR) Gertrude B. Elion Cancer Research Award and the American Lebanese and Syrian Associated Charities (ALSAC) of SJCRH. Support was also provided by NCI grants to the Children's Oncology Group, including CA98543, CA98413 and CA114766. L.H. was supported by the Swedish Research Council. S.P.H. is the Ergen Family Chair in Pediatric Cancer. M.L.L. is a Clinical Scholar in the Leukemia Lymphoma Society and supported by the Frank A. Campini Foundation. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick's Scholar. M.L.L. and E.D.-F. were supported by the Team Connor Foundation, and S.N.P. was supported by 5R25CA023944 from NCI. This paper is dedicated to Henry 'Hank' Schueler who died from complications of hypodiploid ALL and whose Foundation is dedicated to finding a cure for hypodiploid ALL in his memory and to James B. Nachman who was instrumental in the genesis of this project and who recently passed away.

Author information

Author notes

    • Samir N Patel
    •  & Susan L Heatley

    Present addresses: Weill Cornell Medical College, Cornell University, New York, New York, USA (S.N.P.) and Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia (S.L.H.).

    • Linda Holmfeldt
    •  & Lei Wei

    These authors contributed equally to this work.

Affiliations

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

    • Linda Holmfeldt
    • , Lei Wei
    • , Debbie Payne-Turner
    • , Michelle Churchman
    • , Anna Andersson
    • , Shann-Ching Chen
    • , Kelly McCastlain
    • , Jing Ma
    • , Samir N Patel
    • , Susan L Heatley
    • , Letha A Phillips
    • , Guangchun Song
    • , David W Ellison
    • , Sheila A Shurtleff
    • , Susana C Raimondi
    • , James R Downing
    •  & Charles G Mullighan
  2. Department of Pediatrics, University of California School of Medicine, San Francisco, California, USA.

    • Ernesto Diaz-Flores
    •  & Mignon L Loh
  3. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Michael Walsh
    • , Ching-Hon Pui
    •  & Raul C Ribeiro
  4. Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Jinghui Zhang
    • , Jared Becksfort
    • , Gang Wu
    • , Matthew Parker
    • , Xiang Chen
    • , Michael Rusch
    • , Erin Hedlund
    • , Robert Huether
    • , Elaine R Mardis
    •  & Richard K Wilson
  5. The Genome Institute at Washington University, St. Louis, Missouri, USA.

    • Li Ding
    • , Charles Lu
    • , Robert S Fulton
    • , Lucinda L Fulton
    • , Yashodhan Tabib
    • , David J Dooling
    • , Kerri Ochoa
    • , Elaine R Mardis
    •  & Richard K Wilson
  6. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Li Ding
    • , Robert S Fulton
    • , Lucinda L Fulton
    •  & David J Dooling
  7. Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.

    • Anna Andersson
  8. Pediatric Cancer Genome Project, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • John Easton
    • , Kristy Boggs
    •  & Bhavin Vadodaria
  9. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Christina Drenberg
    •  & Sharyn Baker
  10. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Deqing Pei
    •  & Cheng Cheng
  11. Princess Margaret Hospital/University Health Network, University of Toronto, Ontario, Canada.

    • Mark Minden
  12. Division of Haematology, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia.

    • Ian D Lewis
    •  & L Bik To
  13. Oncology/Haematology Unit, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.

    • Paula Marlton
  14. Department of Clinical Haematology and Bone Marrow Transplant, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

    • Andrew W Roberts
  15. Section of Hematology/Oncology, University of Chicago Medicine, Chicago, Illinois, USA.

    • Gordana Raca
    •  & Wendy Stock
  16. The Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Geoffrey Neale
  17. Department of Human and Animal Cell Cultures, Deutsche Sammlung von Mikroorganismen und Zellkulturen, Braunschweig, Germany.

    • Hans G Drexler
  18. Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

    • Ross A Dickins
  19. Department of Biostatistics, College of Medicine, University of Florida, Gainesville, Florida, USA. .

    • Meenakshi Devidas
  20. Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Andrew J Carroll
  21. Department of Pathology, College of Medicine, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.

    • Nyla A Heerema
  22. Department of Laboratory Medicine, Seattle Children's Hospital, Seattle, Washington, USA.

    • Brent Wood
  23. Division of Hematologic Pathology, Johns Hopkins Hospital, Baltimore, Maryland, USA.

    • Michael J Borowitz
  24. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

    • Julie M Gastier-Foster
  25. Department of Pathology, Ohio State University, Columbus, Ohio, USA.

  26. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA.

    • Julie M Gastier-Foster
  27. Siteman Cancer Center, Washington University, St. Louis, Missouri, USA.

    • Elaine R Mardis
    •  & Richard K Wilson
  28. Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation and Center for Cancer and Blood Disorders, University of Colorado Denver School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.

    • Stephen P Hunger

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Contributions

L.H., C.G.M., M.L.L. and S.P.H. designed the experiments. L.H. and D.P.-T. prepared patient samples and generated xenografts. L.H., E.D.-F., M.C., K.M., S.N.P., L.A.P. and S.L.H. performed biochemical analyses. C.D. and S.B. performed ex vivo drug studies. L.H. and J.M. analyzed SNP array data. L.H. and J.E. performed transcriptome sequencing. K.B. performed exome sequencing. L.H., D.P.-T. and B.V. performed sequencing validation. L.W., J.Z., L.D., J.B., Y.T., X.C. and C.L. analyzed sequence data. S.-C.C., A.A., G.N. and L.H. analyzed expression microarray data. M.R., E.H., M.P., G.W., R.H. and G.S. provided bioinformatic support. D.P., C.C. and M.D. performed statistical analyses. R.S.F. and L.L.F. supervised whole-genome sequencing data generation. D.J.D. supervised the automated analysis pipeline. S.C.R., A.J.C. and N.A.H. performed cytogenetic analyses. M.W., C.-H.P., M.M., I.D.L., L.B.T., P.M., A.W.R., G.R., W.S., M.L.L., J.M.G.-F., R.C.R., B.W., M.J.B. and S.P.H. provided clinical samples and data. D.W.E. performed pathological analyses. R.A.D. and H.G.D. provided important reagents. L.H. and C.G.M. wrote the manuscript. L.H., L.W., J.Z., L.D., D.P.-T., M.C., A.A., S.-C.C., K.M., J.B., J.M., G.W., G.S., J.E., M.P., X.C., M.R., E.H., C.L., R.S.F., L.L.F., D.J.D., K.O., S.A.S., C.-H.P., E.R.M., R.K.W., J.R.D. and C.G.M. are part of the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Charles G Mullighan.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note and Supplementary Tables 3–6, 9, 13, 16–20, 23, 24 and 27–34 and Supplementary Figures 1–22

Excel files

  1. 1.

    Supplementary Table 1

    Pediatric hypodiploid ALL cohort

  2. 2.

    Supplementary Table 2

    Adult ALL cohort

  3. 3.

    Supplementary Table 7

    Mutations identified by next-generation sequencing

  4. 4.

    Supplementary Table 8

    Structural variations identified by whole genome sequencing

  5. 5.

    Supplementary Table 10

    Regions of copy number alterations and copy-neutral loss-of-heterozygosity in hypodiploid ALL

  6. 6.

    Supplementary Table 11

    Mutations identified by Sanger sequencing in the hypodiploid ALL cohort

  7. 7.

    Supplementary Table 12

    Copy number alterations and mutations

  8. 8.

    Supplementary Table 14

    Differential expression analysis – NH versus masked NH

  9. 9.

    Supplementary Table 15

    Differential expression analysis – LH versus masked LH

  10. 10.

    Supplementary Table 21

    Differential expression analysis – NH versus LH

  11. 11.

    Supplementary Table 22

    Gene set enrichment analysis (GSEA) – NH versus LH

  12. 12.

    Supplementary Table 25

    Single nucleotide variations identified by mRNA seq of NALM-16

  13. 13.

    Supplementary Table 26

    Primer sequences used for targeted gene resequencing and NF1 deletion mapping

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https://doi.org/10.1038/ng.2532