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Acute lymphoblastic leukemia

Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences

Leukemia volume 31, pages 821–828 (2017)Cite this article

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Abstract

The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family. These mutations were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val). In silico modeling revealed that both mutations affect the conformation of this autoregulatory domain. Consistent with this notion, both germline mutations promote TYK2 autophosphorylation and activate downstream STAT family members, which could be blocked with the JAK kinase inhibitor I. These data indicate that germline activating TYK2 mutations predispose to the development of ALL.

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Acknowledgements

We acknowledge Dr Cory Johannessen and Dr Jesse Boehm for cloning the pDONR223-TYK2. We thank Dr Lisenka ELM Vissers, Dr Joep de Ligt and Dr Christian Gilissen for their technical assistance in whole-exome sequencing and bioinformatic analyses. This study was supported by the Dutch Cancer Society (KUN 2009-4298) and KiKa Foundation (KiKa-127 and KiKa-150). EW is a KWF fellow funded by the Dutch Cancer Society, project number KUN2012-5366.

Author contributions

EW, MCJJ, NH, JJMvD and RPK designed the study; MCJJ, VHJvdV, BG, CEVDS, PMH and JJMvD provided clinical samples and data; EW and RPK analyzed whole-exome sequencing data; MVDV performed bioinformatic analyses; EW, SVR and AHAD performed sequence validation; EW, BS, AP and RAW performed cell biological experiments; HV performed in silico modeling; AGK, FNvL and RPK supervised the study; EW, BS and RPK wrote the manuscript. All authors read and commented on the manuscript.

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The funders had no role in study design, data collection and analyses, decision to publish or preparation of the manuscript.

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Author notes

  1. E Waanders, B Scheijen and M C J Jongmans: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    E Waanders, M C J Jongmans, S V van Reijmersdal, A H A van Dijk, R D A Weren, M van de Vorst, N Hoogerbrugge, A Geurts van Kessel & R P Kuiper

  2. Laboratory of Pediatric Oncology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    B Scheijen & F N van Leeuwen

  3. Department of Pathology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    B Scheijen

  4. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    M C J Jongmans

  5. Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands

    H Venselaar

  6. Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland

    A Pastorczak

  7. Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

    C E van der Schoot

  8. Dutch Childhood Oncology Group, The Hague, The Netherlands

    E Sonneveld

  9. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    V H J van der Velden & J J M van Dongen

  10. Department of Pediatrics, Jena University Hospital, Jena, Germany

    B Gruhn

  11. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    P M Hoogerbrugge

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  1. E Waanders
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Correspondence to R P Kuiper.

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Whole-exome sequencing data have been deposited in the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) under EGAS00001001889.

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Waanders, E., Scheijen, B., Jongmans, M. et al. Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences. Leukemia 31, 821–828 (2017). https://doi.org/10.1038/leu.2016.277

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