RESEARCH INTEREST
Chromosomal translocations and gene mutations are frequently associated with the etiology of hematological malignancies. The JAK family of tyrosine kinases comprises four members — JAK1, JAK2, JAK3, and TYK2 — which are involved in cytokine signaling in hematopoietic cells. These proteins play a fundamental role in maintaining normal hematopoiesis by recruiting effectors that regulate cell proliferation and survival.
Activating mutations in JAK2 have been reported in 10% of high-risk acute lymphoblastic leukemia (ALL) cases, making these patients potential candidates for therapeutic interventions with JAK2 inhibitors. ALL is the most common malignancy in childhood and, although most cases respond to treatment, up to 20% of patients relapse, significantly reducing survival rates. Therefore, we analyzed high-risk B-cell ALL samples using next-generation sequencing, with the aim of determining the prevalence of mutations in JAK family receptors in the Spanish population. We found that TP53 and JAK2 mutations are independent prognostic biomarkers in B-cell ALL. In addition, we provided evidence of naturally occurring catalytic loss-of-function variants in TYK2, which affect the response to type I IFN and are associated with reduced TYK2 expression in patients with B-cell ALL.
Furthermore, TYK2 deficiency in mice has been reported to increase susceptibility to Abelson virus-induced B-cell leukemia/lymphoma, linked to a reduced cytotoxic capacity of CD8+ lymphocytes, NK cells, and NKT cells due to decreased IFN-? production. Taken together, these data suggest that TYK2 loss of function in humans is clinically silent, but may predispose individuals to tumor development. Given the importance of maintaining an adequate immune response for effective tumor surveillance, the role of cytokine receptors, JAK proteins, and their target genes is highly relevant.
Our group focuses on the role of TYK2 in infection and malignancy and, more recently, on the study of immune biomarkers of pneumonia outcomes:
Effect of TYK2 deficiency in B cell function: impact in lymphoproliferative diseases. PI19/00096. ISCIII. 2020-2022.
El proyecto busca evaluar si la disminución de la expresión de TYK2 es una característica de las neoplasias linfoproliferativas B (NLPB) humanas, analizar el perfil de expresión génica de las poblaciones esplénicas deficientes en Tyk2 y su capacidad de generar células B memoria y plasmáticas efectoras, estudiar in vivo si un estímulo antigénico continuado induce una NLPB y esclarecer la contribución de cada uno de los linajes T y B a este fenotipo.
Esta ayuda está financiada por el Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 y el ISCIII – Subdirección General de Evaluación y Fomento de la Investigación – y cofinanciadas por el Fondo Europeo de Desarrollo Regional, Programa Operativo Plurirregional de España 2014-2020 (Objetivo temático “Potenciar la investigación, el desarrollo tecnológico y la innovación”; Objetivo Específico “Fomento y generación de conocimiento de frontera y de conocimiento orientado a los retos de la sociedad, desarrollo de tecnologías emergentes”; Actuación “Proyectos de investigación orientados al Reto de Salud, Cambio Demográfico y Bienestar”, y se regirán de acuerdo con el Reglamento (UE) Nº 1303/2013 y de acuerdo al Reglamento (UE) Nº 1301/2013 del Parlamento Europeo y del Consejo, de 17 de diciembre de 2013 sobre Fondo Europeo de Desarrollo Regional.
Estudio de la incidencia de la pérdida de función de la tirosin-quinasa TYK2 en la regulación de la respuesta inmune. PI15/00032. ISCIII. 2016-2018.
Cuesta-Domínguez A, León-Rico D, Álvarez L, Díez B, Bodega-Mayor I, Baños R, Martín-Rey MA, Santos-Roncero M, Gaspar ML, Martín-Acosta P, Almarza E, Bueren JA, Río P, Fernández-Ruiz E. BCR-JAK2 fusion gene drives a myeloproliferative neoplasm in trasplanted mice. The J. Pathol. 2015; 236: 219–228. IF: 7,330(D1). PMID: 25664618. DOI: 10.1002/path.4513.
Galán-Díez M, Arana DM, Serrano-Gómez D, Kremer L, Casasnovas JM, Ortega M, Cuesta-Domínguez A, Corbí AL, Pla J, Fernández-Ruiz E. Candida albicans beta-Glucan Exposure Is Controlled by the Fungal CEK1-Mediated Mitogen-Activated Protein Kinase Pathway That Modulates Immune Responses Triggered through Dectin-1. Infect Immun 2010. 78: 1426-1436. FI: 4,098(Q1). PMID: 20100861. DOI: 10.1128/IAI.00989-09.
Cuesta-Domínguez Á, Ortega M, Ormazábal C, Santos-Roncero M, Galán-Díez M, Steegmann JL, Figuera Á, Arranz E, Vizmanos JL, Bueren JA, Río P, Fernández-Ruiz E. Transforming and Tumorigenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosine-Kinase. PLoS One 2012. FI: 3,730(Q1). PMID: 22384256. DOI: 10.1371/journal.pone.0032451.
Somovilla-Crespo B, Alfonso-Pérez M, Cuesta-Mateos C, Carballo-de Dios C, Beltrán AE, Terrón F, Pérez-Villar JJ, Gamallo-Amat C, Pérez-Chacón G, Fernández-Ruiz E, Zapata JM, Muñoz-Calleja C. Anti-CCR7 therapy exerts a potent anti-tumor activity in a xenograft model of human mantle cell lymphoma. J. Hematol. Oncol. 2013. 6: 89-0. FI: 4,933(Q1). PMID: 24305507. DOI: 10.1186/1756-8722-6-89.
Cruz-Adalia A, Ramirez-Santiago G, Calabia-Linares C, Torres-Torresano M, Feo L, Galán-Díez M, Fernández-Ruiz E, Pereiro E, Guttmann P, Chiappi M, Schneider G, Carrascosa JL, Chichón FJ, Martínez Del Hoyo G, Sánchez-Madrid F, Veiga E. T Cells Kill Bacteria Captured by Transinfection from Dendritic Cells and Confer Protection in Mice. Cell Host Microbe 2014. 15: 611-622. FI: 12,328(Q1). PMID: 24832455. DOI: 10.1016/j.chom.2014.04.006.
