학술논문
Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences
Document Type
Academic Journal
Author
Waanders, E; Scheijen, B; Jongmans, M C J; Venselaar, H; van Reijmersdal, S V; van Dijk, A H A; Pastorczak, A; Weren, R D A; van der Schoot, C E; van de Vorst, M; Sonneveld, E; Hoogerbrugge, N; van der Velden, V H J; Gruhn, B; Hoogerbrugge, P M; van Dongen, J J M; Geurts van Kessel, A; van Leeuwen, F N; Kuiper, R P
Source
Leukemia. April, 2017, Vol. 31 Issue 4, p821
Subject
Language
English
ISSN
0887-6924
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. Leukemia (2017) 31, 821-828; doi: 10.1038/leu.2016.277; published online 22 November 2016
Author(s): E Waanders [1]; B Scheijen [2, 3]; M C J Jongmans [1, 4]; H Venselaar [5]; S V van Reijmersdal [1]; A H A van Dijk [1]; A Pastorczak [...]
Author(s): E Waanders [1]; B Scheijen [2, 3]; M C J Jongmans [1, 4]; H Venselaar [5]; S V van Reijmersdal [1]; A H A van Dijk [1]; A Pastorczak [...]