VENETOCLAX-RESISTANCE INDUCED BY ACTIVATED T CELLS IN CLL CELLS.

SARAPURA MARTINEZ VALERIA JUDITH; ELIAS ESTEBAN ENRIQUE; COLADO ANA; CORDINI, GREGORIO; BEZARES RAIMUNDO FERNANDO; FERNANDEZ GRECCO HORACIO; CUSTIDIANO, MARÍA DEL ROSARIO; JULIO SANCHEZ AVALOS; GARATE GONZALO MARTÍN; PAVLOVSKY, MIGUEL A.; BORGE MERCEDES; GIORDANO, MIRTA; GAMBERALE ROMINA

Encuentro; 4 LAG-CLL meeting; 2022

Latin american group on CLL (LAG-CLL)

VENETOCLAX-RESISTANCE INDUCED BY ACTIVATEDT CELLS IN CLL CELLS. Valeria Judith Sarapura Martinez, Esteban Elias, Ana Colado, GregorioCordini, Raimundo Fernando Bezares, Horacio Fernandez Grecco, RosarioCustidiano, Julio Cesar Sanchez Avalos, Gonzalo Garate, Miguel A. Pavlovsky,Mercedes Borge, Mirta Giordano, Romina Gamberale. 4th Latin American Group on CLL meeting.May 20-21, 2022AbstractVenetoclax treatment has demonstrated efficacy and a safety profile in chronic lymphocytic leukemia (CLL) patients, howeverthe emergence of resistant cells is a current complication. We and others, previously reported that the activation ofCLL cells by signals that mimic microenvironment stimuli favors the upregulation of anti-apoptotic proteins from B celllymphoma-2 (BCL-2) family that are not targeted by venetoclax, reducing malignant cell sensitivity to the drug. We herestudied venetoclax-resistant CLL cells generated in vitro by autologous activated T lymphocytes, and found that they showedan aggressive phenotype characterized by increased expression of activation and proliferation markers. Moreover, survivingcells expressed high levels of B cell lymphoma-extra-large (BCL-XL) and/or myeloid cell leukemia-1 (MCL-1), and a sustainedresistance 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 ofleukemic cells with this aggressive phenotype, and were able to restore CLL sensitivity to venetoclax. Our data highlight anovel combination to overcome resistance to venetoclax in CLL.