TYK2 Variants in B-Acute Lymphoblastic Leukaemia.

Fecha de publicación: 28/11/2020 Fecha Ahead of Print: 28/11/2020

Autores de IIS La Fe

Eva Barragán González

Autor

Participantes ajenos a IIS La Fe

Turrubiartes-Martínez E
Bodega-Mayor I
Delgado-Wicke P
Molina-Jiménez F
Casique-Aguirre D
González-Andrade M
Rapado I
Camós M
Díaz-de-Heredia C
Ramírez-Orellana M
Aguado B
Figuera Á
Martínez-López J
Fernández-Ruiz E

Grupos

Hematología y Hemoterapia

Investigador Principal

Javier De La Rubia Comos

Abstract

B-cell precursor acute lymphoblastic leukaemia (B-ALL) is a malignancy of lymphoid progenitor cells with altered genes including the Janus kinase (JAK) gene family. Among them, tyrosine kinase 2 (TYK2) is involved in signal transduction of cytokines such as interferon (IFN) a/ß through IFN-a/ß receptor alpha chain (IFNAR1). To search for disease-associated TYK2 variants, bone marrow samples from 62 B-ALL patients at diagnosis were analysed by next-generation sequencing. TYK2 variants were found in 16 patients (25.8%): one patient had a novel mutation at the four-point-one, ezrin, radixin, moesin (FERM) domain (S431G) and two patients had the rare variants rs150601734 or rs55882956 (R425H or R832W). To functionally characterise them, they were generated by direct mutagenesis, cloned in expression vectors, and transfected in TYK2-deficient cells. Under high-IFNa doses, the three variants were competent to phosphorylate STAT1/2. While R425H and R832W induced STAT1/2-target genes measured by qPCR, S431G behaved as the kinase-dead form of the protein. None of these variants phosphorylated STAT3 in in vitro kinase assays. Molecular dynamics simulation showed that TYK2/IFNAR1 interaction is not affected by these variants. Finally, qPCR analysis revealed diminished expression of TYK2 in B-ALL patients at diagnosis compared to that in healthy donors, further stressing the tumour immune surveillance role of TYK2.

Datos de la publicación

ISSN/ISSNe:: 2073-4425, 2073-4425
Tipo:: Article
Páginas:: -
DOI:: 10.3390/genes11121434
Factor de Impacto:: 1,337 SCImago ℠
Cuartil:: Q2 SCImago ℠

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Métricas

Filiaciones

Turrubiartes-Martínez E:: Molecular Biology Unit, University Hospital La Princesa and Research Institute (IIS-IP), Diego de León 62, 28006 Madrid, Spain
Bodega-Mayor I:: Molecular Biology Unit, University Hospital La Princesa and Research Institute (IIS-IP), Diego de León 62, 28006 Madrid, Spain
Delgado-Wicke P:: Molecular Biology Unit, University Hospital La Princesa and Research Institute (IIS-IP), Diego de León 62, 28006 Madrid, Spain
Molina-Jiménez F:: Molecular Biology Unit, University Hospital La Princesa and Research Institute (IIS-IP), Diego de León 62, 28006 Madrid, Spain
Casique-Aguirre D:: School of Medicine, Latin University of Mexico (ULM), Avenida San Jose 100, 38085 Celaya, Mexico
González-Andrade M:: Biosensors and Molecular Modelling Lab, Biochemistry Department, Autonomous National University of México (UNAM), 04510 Mexico City, Mexico
Rapado I:: Haematology Department, University Hospital 12 Octubre and Research Institute (i+12), Avenida de Córdoba s/n., 28041 Madrid, Spain
Camós M:: Haematology Department, University Hospital Sant Joan de Déu and Research Institute (IRSJD), Passeig Sant Joan de Déu 2, 08950 Esplugues de Llobregat, Spain
Díaz-de-Heredia C:: Paediatric Haematology and Oncology Department, University Hospital Vall d'Hebron and Research Institute (VHIR), Passeig de la Vall d'Hebron 119-129, 08035 Barcelona, Spain
Barragán E:: Instituto de Investigación. Molecular Biology Lab, Clinical Analysis Department, University and Polytechnic Hospital and IIS La Fe, Avenida de Fernando Abril Martorell 106, 46026 Valencia, Spain
Ramírez-Orellana M:: Paediatric Haematology and Oncology Department, Paediatric University Hospital Niño Jesús (IIS-IP), Avenida de Menéndez Pelayo 65, 28009 Madrid, Spain
Aguado B:: Haematology Department, University Hospital La Princesa (IIS-IP), 28006 Madrid, Spain
Figuera Á:: Haematology Department, University Hospital La Princesa (IIS-IP), 28006 Madrid, Spain
Martínez-López J:: Haematology Department, University Hospital 12 Octubre and Research Institute (i+12), Avenida de Córdoba s/n., 28041 Madrid, Spain

Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain

Faculty of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
Fernández-Ruiz E:: Molecular Biology Unit, University Hospital La Princesa and Research Institute (IIS-IP), Diego de León 62, 28006 Madrid, Spain

Faculty of Medicine, Autonomous University of Madrid, 28049 Madrid, Spain

Keywords

B-cell precursor acute lymphoblastic leukaemia, IFNa, IFNa/ß receptor alpha chain (IFNAR1), next-generation sequencing, TYK2 expression, TYK2 variants, immune surveillance, molecular dynamics