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Projects. Life and Earth Sciences

Inhibition of the protein that regulates SLC4A2 cell ion metabolism as a new therapy in leukaemia, lymphoma and myeloma

Lead Researcher:
José Ángel Martínez-Climent

Research Centre:
Centro de Investigación Médica Aplicada de la Universidad de Navarra. Pamplona.

Abstract: 

José Ángel Martínez-ClimentIn spite of the breakthroughs in treating leukaemia, lymphomas and myelomas, a large percentage of patients do not respond in a satisfactory way to current therapies, making it necessary to explore new therapeutic approaches. Previous results in our group indicate that mice lacking the cell ion metabolism protein SLC4A2 (AE2) present a reduced number of regulating T lymphocytes (Tregs). Given that Tregs repress the antitumor immune response, our data suggest that AE2 may be a therapeutic target in cancer. To evaluate this hypothesis, we generated peptides that interact with the third extracellular loop of AE2. Mechanistically, peptides deregulate the function of AE2, blocking the transmembrane exchange of Cl- and HCO3- and inducing changes in the intracellular pH (pHi). The most active peptide (p17AE2) reduces the pHi in Tregs, inducing their mass apoptosis. p17AE2 also induced apoptosis in 64% of cell lines derived from patients with leukaemia, B lymphoma and myeloma, while in 44% of primary samples from patients, it hardly affected the viability of non-tumoral B lymphocytes. In this project we plan to test whether p17AE2 has a dual therapeutic effect in lymphoid neoplasias by i) direct induction of apoptosis in tumoral B lymphoid cells; and ii) activation of the antitumour immune response by eliminating the Tregs. These results will allow us to establish a test of the concept of pharmacological inhibition of the cell ion metabolism regulating mechanism as a new therapy in cancer.


Researcher's web address:
https://www.cima.es/labs/view/27/molecular-oncology-lab-108/summary/29



José Ángel Martínez-Climent

He gained the qualification of Specialist Doctor in Paediatric Haematological Oncology as an intern in Hospital La Fe, Valencia, in 1992. He then made a post-doctoral visit to the University of Chicago under Janet D. Rowley, working on the genetic characterisation of leukaemia to obtain the qualification of Doctor of Medicine in 1996. On his return he worked as Assistant Doctor in the Departamento de Hematología y Oncología del Hospital Clínico Universitario de Valencia, where he founded the cancer haematology cytogenetics laboratory (1996-2004). In 2001 he made a long visit to the University of California in San Francisco (UCSF), working with Daniel Pinkel on the genomic study of lymphomas. In 2004 as a Ramón y Cajal investigator he joined the Oncology Department of the Applied Medicine Research Centre (CIMA) of the University of Navarre in Pamplona, where he is now a Senior Investigator and Tenured Professor of Medicine. His line of research centres on studying the functional biology of leukaemia, lymphomas and myelomas in murine experimental models, with the aim of developing new targeted therapies. He has published83 papers in scientific journals, 20 as the first signer and 23 as the senior author, and he has directed 11 doctoral theses.


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