| Literature DB >> 27733777 |
E Waanders1, B Scheijen2,3, M C J Jongmans1,4, H Venselaar5, S V van Reijmersdal1, A H A van Dijk1, A Pastorczak6, R D A Weren1, C E van der Schoot7, M van de Vorst1, E Sonneveld8, N Hoogerbrugge1, V H J van der Velden9, B Gruhn10, P M Hoogerbrugge11, J J M van Dongen9, A Geurts van Kessel1, F N van Leeuwen2, R P Kuiper1.
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.Entities:
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Year: 2016 PMID： 27733777 DOI： 10.1038/leu.2016.277
Source DB: PubMed Journal: Leukemia ISSN： 0887-6924 Impact factor: 11.528