IMEX   05356
INSTITUTO DE MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Chronic lymphocytic leukemia: the effect of novel therapeutic agents on the leukemic clone and non-malignant cells?
Autor/es:
GAMBERALE ROMINA
Reunión:
Congreso; reunión anual de biosciencias SAIC 2020; 2020
Institución organizadora:
SAIC
Resumen:
Chronic lymphocytic leukemia (CLL) is the most commonadult leukemia in western countries. It is characterizedby the presence of malignant B cells in peripheral bloodand lymphoid tissues. The approval of multiple new targetedagents has allowed important advances in therapeuticmanagement of CLL patients, improving clinicaloutcomes and quality of life. However, CLL is still an incurabledisease. Lymphoid tissues act as survival niches,where leukemic cells receive signals through the B cellreceptor (BCR) and signals from non-malignant cells thatfavor leukemic cell accumulation. Our group has beenworking with different novel therapeutic agents for CLLpatients: inhibitors of the BCR-associated kinases (BCRKIs),and the selective BCL-2 inhibitor, venetoclax. Wefirst confirmed that peripheral blood leukemic cells fromCLL patients are very sensitive to venetoclax in vitro ina dose-dependent manner, while T cells, NK cells, andmonocytes are less sensitive to the drug. We also foundthat CLL cells that have received survival signals fromthe tumor microenvironment, such as those triggeredby autologous activated T cells, are less responsive tovenetoclax due to the upregulation of anti-apoptotic proteinsMCL-1 or BCL-XL, which are not targeted by thedrug. Venetoclax-resistant leukemic cells are characterizedby high levels of activation and proliferation markers,increased PD-1 expression and show resistance toa second treatment with the drug. Finally, we found thatBCR-KIs entospletinib and idelalisib by impairing T cellactivation, prevent the generation of CLL cells with anaggressive phenotype and, more importantly, completelyrestore the sensitivity to venetoclax. Altogether, these invitro evidences highlight the relevance of the tumor microenvironmentin the generation of venetoclax-resistantCLL cells and provide an interesting rationale for combiningvenetoclax with entospletinib or idelalisib to reducethe emergence of drug resistance in vivo.