Details

Autor(en) / Beteiligte

• Elias, Esteban Enrique
• Sarapura Martinez, Valeria Judith
• Amondarain, Mikele
• Colado, Ana
• Cordini, Gregorio
• Bezares, Raimundo Fernando
• Fernandez Grecco, Horacio
• Custidiano, Maria del Rosario
• Sánchez Ávalos, Julio César
• Garate, Gonzalo
• Pavlovsky, Miguel A.
• Borge, Mercedes
• Giordano, Mirta
• Gamberale, Romina

Titel

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

Ist Teil von

• Cancer Immunology, Immunotherapy, 2022-04, Vol.71 (4), p.979-987

Ort / Verlag

Berlin/Heidelberg: Springer Berlin Heidelberg

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.