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

E Waanders, B Scheijen, M C J Jongmans, H Venselaar, S V van Reijmersdal, A H A van Dijk, A Pastorczak, R D A Weren, C E van der Schoot, M van de Vorst, E Sonneveld, N Hoogerbrugge, V H J van der Velden, B Gruhn, P M Hoogerbrugge, J J M van Dongen, A Geurts van Kessel, F N van Leeuwen, R P Kuiper

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)821-828
Number of pages8
Issue number4
Publication statusPublished - Apr 2017
Externally publishedYes


  • Alleles
  • Amino Acid Substitution
  • Exome
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Germ-Line Mutation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Models, Molecular
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • STAT Transcription Factors/metabolism
  • TYK2 Kinase/chemistry


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