Biological, cellular and molecular monitoring in haematology-oncology

Chromosomal translocations that produce fusion proteins are generally associated with the aetiology of haematologic malignancies. The search for specific tyrosine-kinase inhibitors of fusion proteins is an area of active research, following the success of imatinib-based therapy. We have described the transforming and tumourigenic activity of a new fusion protein, BCR-JAK2, obtained from a patient with acute lymphoblastic leukaemia (ALL).

This chimeric protein involves the fusion of the oligomerisation domain of BCR with the tyrosine-kinase domain of JAK2. JAK2 is a non-receptor tyrosine-kinase that mediates the signalling of different cytokine receptors and is crucial for normal haematopoiesis by recruiting effectors that act further down in proliferation and survival signalling. Our group was able to prove that cells expressing BCR-JAK2 developed tumours when injected subcutaneously into immunodeficient mice. In addition, using bone marrow precursors transplanted into a mouse transplant model, we demonstrated that BCR-JAK2 is the triggering force of a myeloproliferative syndrome with a fatal outcome.

These findings support the use of this model as a relevant preclinical tool to validate new therapeutic approaches with JAK2 inhibitors. This therapy justifies further research on the use alone or in combination with standard chemotherapy in the treatment of human cancers with high JAK2 activity. It has recently been published that 10% of high-risk paediatric acute lymphoblastic leukaemia cases present activating mutations and could be candidates for therapeutic interventions with JAK2 inhibitors.

ALL is the most common neoplasm in childhood and although most cases respond to treatment, 20% relapse, shortening survival. We therefore want to analyse high-risk ALL samples using next-generation sequencing technology (NGS) to determine the percentage of mutations in the JAK kinase family in the Spanish population. For this purpose, ALL samples will be obtained from hospitals throughout the country. The analysis of mutations will be correlated with clinical parameters to evaluate their prognostic value. Moreover, those mutations that may alter receptor function will be analysed in in vivo tests with mutated constructions to describe their effect on subsequent signalling pathways to the receptor.

Miembros del equipo

Area3_Linea5_G45_Dra-Fernandez-Ruiz

Jefe de grupo:

Elena Fernández Ruiz

Hospital Univeristario La Princesa

Other team members. Hospital Universitario La Princesa:

  • Irene Bodega Mayor
  • María Rosa Carracedo Rodríguez
  • Matilde Santos Roncero
  • Edgar Alejandro Turrubiartes Martínez

Fernández Ruiz, Elena. 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 transplanted 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.