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

17th national competition for scientific and technical research

Metabolism and cancer

Senior Researcher : José Ángel Martínez-Climent

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Research Centre or Institution : Centro de Investigación Médica Aplicada de la Universidad de Navarra


In 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.

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