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

Waanders, Esmé; Scheijen, Blanca; Jongmans, Marjolijn C.J.; Venselaar, Hanka; Reijmersdal, Simon V. van; Dijk, Anke H.A. van; Pastorczak, Agata; Weren, Robbert D.A.; Schoot, C. Ellen van der; Vorst, J.M. van de; Sonneveld, Edwin; Hoogerbrugge, Nicoline; Velden, V.H. van der; Gruhn, Bernd; Hoogerbrugge, Peter M.; Dongen, Jacques J. M. van; Kessel, A.H.M. Geurts van; Leeuwen, Frank N. van; Kuiper, Roland P.

doi:10.1038/leu.2016.277

Cited by 37 publications

(37 citation statements)

References 59 publications

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“…In a boy with two primary leukemia occurrences (Case #05), a mutation in TYK2 was identified (p.Pro760Leu), located in the DPG motif of the pseudokinase domain. Interestingly, as we published earlier (28), another mutation in TYK2 (p.Gly761Val) was found in a second patient with two primary leukemia occurrences. Both mutations promote TYK2 autophosphorylation and activate downstream STAT family members.…”

Section: Possible Novel Candidate Genessupporting

confidence: 65%

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High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

Diets

Waanders

Ligtenberg

et al. 2018

Clinical Cancer Research

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In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer. To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome. Four patients carried causative mutations in a known cancer-predisposing gene: and ( = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (-based Rubinstein-Taybi syndrome, -based Coffin-Siris syndrome,-based Baraitser-Winter syndrome, and -based Weaver syndrome). In addition, we identified two genes, and , which are possibly involved in genetic cancer predisposition. In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. .

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Section: Possible Novel Candidate Genessupporting

confidence: 65%

“…Both mutations promote TYK2 autophosphorylation and activate downstream STAT family members. Because activation of the JAK-STAT pathway is an important oncogenic event in the pathogenesis of leukemia, these mutations in TYK2 may contribute to the development of leukemia (28).…”

Section: Possible Novel Candidate Genesmentioning

confidence: 99%

High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

Diets

Waanders

Ligtenberg

et al. 2018

Clinical Cancer Research

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“…JAK/ STAT signaling components are frequently altered in cancers, and considerable effort is directed toward the development of specific inhibitors for tumor therapy (21)(22)(23)(24). TYK2 inhibitors are considered for the treatment of inflammatory diseases and tumor therapy (25)(26)(27)(28)(29)(30)(31)(32). However, to realize their full potential and to identify harmful side effects, a better understanding of how TYK2 regulates NK cell function and antitumor activity is required.…”

mentioning

confidence: 99%

NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity

Simonović

Witalisz-Siepracka

Meissl

et al. 2019

The Journal of Immunology

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Tyrosine kinase 2 (TYK2) is a widely expressed receptor-associated kinase that is involved in signaling by a variety of cytokines with important immune regulatory activities. Absence of TYK2 in mice results in impaired NK cell maturation and antitumor activity, although underlying mechanisms are largely unknown. Using conditional ablation of TYK2 in NK cells we show that TYK2 is required for IFN-g production by NK cells in response to IL-12 and for an efficient immune defense against Listeria monocytogenes. Deletion of TYK2 in NK cells did not impact NK cell maturation and IFN-g production upon NK cell activating receptor (actR) stimulation. Similarly, NK cell-mediated tumor surveillance was unimpaired upon deletion of TYK2 in NK cells only. In line with the previously reported maturation-associated Ifng promoter demethylation, the less mature phenotype of Tyk2 2/2 NK cells correlated with an increased CpG methylation at the Ifng locus. Treatment with the DNA hypomethylating agent 5-aza-2-deoxycytidine restored the ability of Tyk2 2/2 NK cells to produce IFN-g upon actR but not upon IL-12 stimulation. NK cell maturation was dependent on the presence of TYK2 in dendritic cells and could be rescued in Tyk2-deficient mice by treatment with exogenous IL-15/IL-15Ra complexes. IL-15 treatment also rescued the in vitro cytotoxicity defect and the impaired actR-induced IFN-g production of Tyk2 2/2 NK cells. Collectively, our findings provide the first evidence, to our knowledge, for a key role of TYK2 in the host environment in promoting NK cell maturation and antitumor activity.

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“…Notably, the PID phenotypes depend on the affected gene and mutation, ranging from mild phenotypes involving TYK2 , a moderate hyper-IgE syndrome for STAT3 and severe combined immunodeficiency (SCID) in case of JAK3 mutations ( 41 ). It is only recently, that mutations in TYK2 , a JAK kinase family member, were found in the germline of patients presenting with a second primary leukemia, causing constitutive JAK signaling and a propensity for developing leukemia ( 42 ).…”

Section: Pid and Cancer Genesmentioning

confidence: 99%

Genes at the Crossroad of Primary Immunodeficiencies and Cancer

et al. 2018

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Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders affecting one or multiple components of the innate and/or adaptive immune system. Currently, over 300 underlying genetic defects have been discovered. The most common clinical findings in patients with PIDs are infections, autoimmunity, and malignancies. Despite international efforts, the cancer risk associated with PIDs, given the heterogeneous character of this group of diseases, is difficult to estimate. The diverse underlying mechanisms of cancer in PID add another layer of complexity. Treatment of cancer within a context of PID is complicated by serious toxicities and long-term effects, including second malignancies. This review will focus on the little-known crossroad between PID and cancer genes and the value thereof for directing future research on our understanding of cancer in PID and for the identification of early cancer biomarkers in PID patients.

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

Cited by 37 publications

References 59 publications

High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity

Genes at the Crossroad of Primary Immunodeficiencies and Cancer

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