Venetoclax-resistant CLL cells show a highly activated and proliferative phenotype.

Autor: Elias EE; Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Ciudad Autónoma de Buenos Aires, Argentina., Sarapura Martinez VJ; Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Ciudad Autónoma de Buenos Aires, Argentina., Amondarain M; Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Ciudad Autónoma de Buenos Aires, Argentina., Colado A; Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Ciudad Autónoma de Buenos Aires, Argentina., Cordini G; Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Ciudad Autónoma de Buenos Aires, Argentina.; Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina., Bezares RF; Hospital General de Agudos Dr. Teodoro Álvarez, Buenos Aires, Argentina., Fernandez Grecco H; Sanatorio Municipal Dr. Julio Méndez, Buenos Aires, Argentina., Custidiano MDR; Instituto Alexander Fleming, Buenos Aires, Argentina., Sánchez Ávalos JC; Instituto Alexander Fleming, Buenos Aires, Argentina., Garate G; Hospital Alemán, Buenos Aires, Argentina., Pavlovsky MA; FUNDALEU, CABA, Buenos Aires, Argentina., Borge M; Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Ciudad Autónoma de Buenos Aires, Argentina.; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay, 2155, Buenos Aires, Argentina., Giordano M; Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Ciudad Autónoma de Buenos Aires, Argentina.; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay, 2155, Buenos Aires, Argentina., Gamberale R; Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Ciudad Autónoma de Buenos Aires, Argentina. rominagamberale@gmail.com.; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay, 2155, Buenos Aires, Argentina. rominagamberale@gmail.com.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2022 Apr; Vol. 71 (4), pp. 979-987. Date of Electronic Publication: 2021 Aug 31.
DOI: 10.1007/s00262-021-03043-x
Abstrakt: Venetoclax treatment has demonstrated efficacy and a safety profile in chronic lymphocytic leukemia (CLL) patients, however the emergence of resistant cells is a current complication. We and others, previously reported that the activation of CLL cells by signals that mimic microenvironment stimuli favors the upregulation of anti-apoptotic proteins from B cell lymphoma-2 (BCL-2) family that are not targeted by venetoclax, reducing malignant cell sensitivity to the drug. We here studied venetoclax-resistant CLL cells generated in vitro by autologous activated T lymphocytes, and found that they showed an aggressive phenotype characterized by increased expression of activation and proliferation markers. Moreover, surviving cells expressed high levels of B cell lymphoma-extra-large (BCL-XL) and/or myeloid cell leukemia-1 (MCL-1), and a sustained resistance to a second treatment with the drug. Interestingly, the spleen tyrosine kinase (SYK) inhibitor entospletinib, and the phosphoinositide 3-kinase delta (PI3Kδ) inhibitor idelalisib, reduced T cell activation, impaired the generation of leukemic cells with this aggressive phenotype, and were able to restore CLL sensitivity to venetoclax. Our data highlight a novel combination to overcome resistance to venetoclax in CLL.
(© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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