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Mutation analysis of Son of Sevenless in juvenile myelomonocytic leukemia

Leukemia volume 21, pages 1108–1109 (2007)Cite this article

Ras proteins are molecular switches that cycle between inactive GDP-bound and active GTP-bound states.1 Growth factors activate Ras by recruiting the nucleotide exchange factor Son of Sevenless (SOS1) to the plasma membrane.2, 3 Ras signaling has profound consequences for the cell and unregulated Ras activation is a hallmark of cancer. Germline mutations of genes activating this pathway can also cause developmental disorders, such as Noonan (PTPN11, KRAS), Costello (HRAS), and cardio-facio-cutaneous syndromes (KRAS, BRAF, MEK1/2), as well as neurofibromatosis type 1 (NF1).1

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder (MPD) characterized by leukocytosis, tissue infiltration by malignant cells, and in vitro hypersensitivity of myeloid progenitors to granulocyte–macrophage colony stimulating factor.4, 5 The incidence of JMML is increased in children with neurofibromatosis type 1 (NF1).5 NF1, which is diagnosed in ∼11% of all JMML cases, is an autosomal dominant cancer predisposition syndrome caused by mutations of NF1 coding for neurofibromin, a GTPase activating protein (GAP) for Ras.5 JMML cells from patients with NF1 show biallelic NF1 inactivation and elevated Ras·GTP levels.5 Approximately 25% of JMML cases have somatic RAS mutations, which are identified in patients who do not have NF1.5 These data and studies in mouse models underscore a crucial role of hyperactive Ras in the pathogenesis of JMML.5

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Acknowledgements

This work was supported by US Public Health Service Grants R37CA49152 and R01CA11945 (KS and BN) from the National Institutes of Health. The authors wish to thank all of the patients, families, and referring physicians who contributed samples to the investigators. We thank Angelika Diem and Marco Teller for their excellent technical assistance. We are grateful to Dr Mwe Mwe Chao for critical comments.

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Authors and Affiliations

  1. Department of Pediatrics, University of Freiburg, Freiburg, Germany

    C P Kratz, C M Niemeyer, C Flotho & B Strahm

  2. Department of Structural Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany

    C Thomas

  3. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

    S Bauhuber, V Matejas & M Zenker

  4. Division of Pediatric Hematology and Oncology, University Children's Hospital Zurich, Zurich, Switzerland

    E Bergsträsser

  5. Department of Pediatrics and the Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA

    N J Flores & M L Loh

  6. Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria

    O Haas

  7. Department of Pediatrics, Skejby Hospital, Aarhus University, Aarhus, Denmark

    H Hasle

  8. Dutch Childhood Oncology Group, the Hague, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands

    M M van den Heuvel-Eibrink

  9. Harvard Partners Center for Genetics and Genomics and Harvard Medical School, Boston, MA, USA

    R S Kucherlapati & A E Roberts

  10. Department of Pediatrics, University of Tübingen, Tübingen, Germany

    P Lang

  11. Division of Genetics, Department of Medicine, Children's Hospital Boston and Harvard Medical School, Boston, MA, USA

    A E Roberts

  12. Department of Pediatric Hematology/Oncology, Charles University, University Hospital Motol, Prague, Czech Republic

    J Starý

  13. Division of Hematology/Oncology, Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    K D Swanson & B Neel

  14. Department of Pediatrics, St Anna Children's Hospital, Vienna, Austria

    M Trebo

  15. Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy

    M Zecca & F Locatelli

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  1. C P Kratz
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on behalf of the European Working Group on Childhood MDS (EWOG-MDS)

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Correspondence to C P Kratz.

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Kratz, C., Niemeyer, C., Thomas, C. et al. Mutation analysis of Son of Sevenless in juvenile myelomonocytic leukemia. Leukemia 21, 1108–1109 (2007). https://doi.org/10.1038/sj.leu.2404620

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