TYK2 Variants in B-Acute Lymphoblastic Leukaemia
Turrubiartes-Martínez, Edgar (Instituto de Investigación Hospital Universitario de la Princesa)
Bodega-Mayor, Irene (Instituto de Investigación Hospital Universitario de la Princesa)
Delgado-Wicke, Pablo (Instituto de Investigación Hospital Universitario de la Princesa)
Molina-Jiménez, Francisca (Instituto de Investigación Hospital Universitario de la Princesa)
Casique-Aguirre, Diana (Latin University of Mexico)
González-Andrade, Martín (Universidad Nacional Autónoma de México)
Rapado, Inmaculada (Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12))
Camós, Mireia (University Hospital Sant Joan de Déu)
Díaz de Heredia, Cristina (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Barragán, Eva (Hospital Universitari i Politècnic La Fe (València))
Ramírez, Manuel (Hospital Infantil Universitario Niño Jesús (Madrid))
Aguado, Beatriz (Instituto de Investigación Hospital Universitario de la Princesa)
Figuera, Ángela (Instituto de Investigación Hospital Universitario de la Princesa)
Martínez-López, Joaquín (Complutense University of Madrid)
Fernández-Ruiz, Elena (Universidad Autónoma de Madrid)
Universitat Autònoma de Barcelona

Data:	2020
Resum:	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) α/β through IFN−α/β 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-IFNα 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.
Ajuts:	Instituto de Salud Carlos III PI19/00096 Ministerio de Economía y Competitividad PI15/00032
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	B-cell precursor acute lymphoblastic leukaemia ; TYK2 variants ; IFNα ; IFNα/β receptor alpha chain (IFNAR1) ; Next-generation sequencing ; Molecular dynamics ; TYK2 expression ; Immune surveillance
Publicat a:	Genes, Vol. 11 (november 2020) , ISSN 2073-4425

DOI: 10.3390/genes11121434
PMID: 33260630

16 p, 2.4 MB

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