title: Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences.
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.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Waanders
authors.affiliation: Laboratory of Pediatric Oncology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.|Department of Pathology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Scheijen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.|Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M C J
authors.initials: MC
authors.lastname: Jongmans
authors.affiliation: Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: S V
authors.initials: SV
authors.lastname: van Reijmersdal
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: A H A
authors.initials: AH
authors.lastname: van Dijk
authors.affiliation: Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Pastorczak
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: R D A
authors.initials: RD
authors.lastname: Weren
authors.affiliation: Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C E
authors.initials: CE
authors.lastname: van der Schoot
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van de Vorst
authors.affiliation: Dutch Childhood Oncology Group, The Hague, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Sonneveld
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: V H J
authors.initials: VH
authors.lastname: van der Velden
authors.affiliation: Department of Pediatrics, Jena University Hospital, Jena, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Gruhn
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: J J M
authors.initials: JJ
authors.lastname: van Dongen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Geurts van Kessel
authors.affiliation: Laboratory of Pediatric Oncology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: F N
authors.initials: FN
authors.lastname: van Leeuwen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: R P
authors.initials: RP
authors.lastname: Kuiper
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D050791:STAT Transcription Factors / Q000378:metabolism; D053634:TYK2 Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D050791:STAT Transcription Factors; D053634:TYK2 Kinase