The genomic landscape of juvenile myelomonocytic leukemia

Journal name:
Nature Genetics
Volume:
47,
Pages:
1326–1333
Year published:
DOI:
doi:10.1038/ng.3400
Received
Accepted
Published online
Corrected online

Abstract

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

At a glance

Figures

  1. Mutations identified by exome sequencing.
    Figure 1: Mutations identified by exome sequencing.

    Data for 29 patients who were subjected to whole-exome sequencing are displayed. The results for each patient are presented in a single condensed column, including mutations identified in the germline and at diagnosis (black type) and relapse (red type). Germline mutations are presented by color in the bottom half of the box for any given gene, and somatic mutations are presented in the top half. Mutations only present at relapse are denoted with vertically striped bars. LOH for a single gene is annotated with a thin black rectangle outlining the mutation. Somatic compound heterozygous mutations are noted with a white circle. WBC, white blood cell; TF, transcription factor.

  2. Circos plot of samples with at least two mutations.
    Figure 2: Circos plot of samples with at least two mutations.

    Using data from whole-exome sequencing and targeted resequencing, patients with at least two mutations are depicted. Associations between genomic alterations in the same patient are marked by connecting bands, with the width of each band proportional to the frequency of the association.

  3. Mutations in SH2B3 decrease expression of LNK.
    Figure 3: Mutations in SH2B3 decrease expression of LNK.

    (a) Compound heterozygous mutations mapping to the PH and SH2 domains are presented for each patient found to harbor SH2B3 lesions by whole-exome sequencing. (b) Immunoblot analysis of whole-cell lysates using antibodies to LNK and β-actin. Commensurate with the allelic fraction of each mutation (UPN1420-relapse, 31%; UPN2531-diagnosis, 37%), the expression of LNK is decreased relative to a healthy contol (WT).

  4. Event-free and overall survival of patients stratified by number of somatic alterations.
    Figure 4: Event-free and overall survival of patients stratified by number of somatic alterations.

    Kaplan-Meier estimated event-free survival (log-rank P = 0.003) (a) and overall survival (log-rank P = 0.002) (b) rates are shown according to the number of somatic alterations at diagnosis.

Change history

Corrected online 07 December 2015
In the version of this article initially published, two patients were stated on page 5 to have been excluded owing to insufficient follow-up data. These patients were included in the final analysis, but two additional patients were excluded owing to the presence of Noonan syndrome. On page 6, monosomy 7 was incorrectly listed as a significant factor in event-free and overall survival, but this factor was no longer significant after removing the patients with Noonan syndrome. The Online Methods incorrectly referred to "Data from patient AAML0122" instead of data from patients enrolled on AAML0122. The errors have been corrected in the HTML and PDF versions of the rticle.

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Author information

  1. These authors contributed equally to this work.

    • Elliot Stieglitz &
    • Amaro N Taylor-Weiner

Affiliations

  1. Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, USA.

    • Elliot Stieglitz,
    • Tiffany Y Chang,
    • Laura C Gelston,
    • Emilio Esquivel,
    • Ariel Yu,
    • Sophie L Archambeault,
    • Kyle Beckman &
    • Mignon L Loh
  2. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Amaro N Taylor-Weiner,
    • Sara Seepo,
    • Mara Rosenberg,
    • Chip Stewart,
    • Gad Getz,
    • Todd R Golub &
    • Kimberly Stegmaier
  3. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Yong-Dong Wang &
    • Yongjin Li
  4. Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

    • Tali Mazor &
    • Joseph F Costello
  5. Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Scott R Olsen
  6. Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.

    • Ghada Abusin
  7. Department of Pediatrics, Johns Hopkins Hospital, Baltimore, Maryland, USA.

    • Patrick A Brown &
    • Clifford M Takemoto
  8. Department of Pediatrics, Emory University School of Medicine, Aflac Cancer and Blood Disorder Center, Atlanta, Georgia, USA.

    • Michael Briones
  9. Department of Pediatrics, Texas Tech University, El Paso, Texas, USA.

    • Benjamin Carcamo
  10. Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington, USA.

    • Todd Cooper
  11. Department of Pediatrics, Stanford School of Medicine, Stanford, California, USA.

    • Gary V Dahl
  12. Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

    • Peter D Emanuel &
    • Y Lucy Liu
  13. Department of Pediatric Hematology Oncology, University of Utah, Salt Lake City, Utah, USA.

    • Mark N Fluchel
  14. Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

    • Rakesh K Goyal
  15. Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Robert J Hayashi
  16. Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Johann Hitzler
  17. Pediatric Hematology Oncology, SSM Cardinal Glennon Children's Medical Center, St. Louis, Missouri, USA.

    • Christopher Hugge
  18. Division of Pediatric Hematology Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.

    • Yoav H Messinger
  19. Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.

    • Donald H Mahoney Jr
  20. Pediatric Hematology Oncology, Pediatric Specialists of Lehigh Valley Hospital, Bethlehem, Pennsylvania, USA.

    • Philip Monteleone
  21. Pediatric Bone Marrow Transplant Program, Oregon Health and Science University, Portland, Oregon, USA.

    • Eneida R Nemecek
  22. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Philip A Roehrs
  23. Division of Pediatric Oncology, Children's National Medical Center, Washington, DC, USA.

    • Reuven J Schore
  24. Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

    • Kimo C Stine
  25. Department of Pediatrics, Georgetown University, Washington, DC, USA.

    • Jeffrey A Toretsky
  26. Department of Oncology, Georgetown University, Washington, DC, USA.

    • Jeffrey A Toretsky
  27. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

    • Adam B Olshen
  28. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.

    • Adam B Olshen
  29. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Jing Ma &
    • Tanja A Gruber
  30. Department of Statistics, Children's Oncology Group, Monrovia, California, USA.

    • Robert B Gerbing
  31. Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Todd A Alonzo
  32. Harvard Medical School, Boston, Massachusetts, USA.

    • Gad Getz
  33. Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Gad Getz
  34. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Todd R Golub &
    • Kimberly Stegmaier
  35. Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Todd R Golub &
    • Kimberly Stegmaier
  36. Department of Pediatrics, Benioff Children's Hospital, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

    • Mignon L Loh

Contributions

E.S., L.C.G., T.M., E.E., A.Y., K.B. and S.L.A. performed the experiments. E.S., A.N.T.-W., Y.-D.W., T.M., M.R., A.B.O., Y.L., J.M., R.B.G. and T.A.A. performed data analysis. G.A., M.B., P.A.B., B.C., T.C., G.V.D., P.D.E., M.N.F., R.K.G., R.J.H., J.H., C.H., Y.L.L., Y.H.M., D.H.M., P.M., E.R.N., P.A.R., R.J.S., K.C.S., C.M.T. and J.A.T. contributed reagents, materials and analysis tools. E.S., A.N.T.-W. and M.L.L. wrote the first draft of the manuscript. T.Y.C. performed statistical analysis. J.F.C., C.S., G.G., T.A.G., T.R.G., K.S. and M.L.L. supervised research. S.S. and S.R.O. managed the project. All coauthors contributed to the final version of the manuscript.

Competing financial interests

The authors declare no competing financial interests.

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