G PROTEIN-COUPLED RECEPTOR KINASE 2 (GRK-2) MODULATES THE ACTIVATION AND MIGRATION OF LEUKEMIC AND T CELLS FROM CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS.

C CASSARINO, ; J BERNATOWIEZ, ; SARAPURA MARTÍNEZ VALERIA; B BUONINCONTRO, ; M BERTINI, ; F BEZARES, ; M VERMEULEN,; GAMBERALE ROMINA; M GIORDANO, ; COLADO ANA; M BORGE

Congreso; REUNIÓN CONJUNTA SAIC SAI & FAIC SAFIS 2022; 2022

Leukemic B cell proliferation mainly occurs in the lymph nodes in response to signals provided by the tumor microenvironment, such as CD40L and cytokines secreted by activated T cells. GRK2 regulates B cell homing to lymph nodes by inducing S1PR1 (Sphingosine-1 phosphate receptor-1) downregulation, which allows the lymphocyte to overcome the S1P-mediated retention in the blood, and to follow the chemokine gradient into the tissue. GRK2 also modulates other cellular functions such as activation and survival in different cancer cells. We have previously found that a GRK2 inhibitor, CMPD101 (CMP) increases leukemic-cell migration to S1P without affecting spontaneous or drug-induced apoptosis. Here we aim to expand the study on the effect of GRK2 inhibition in the activation and migration of leukemic and T cells from CLL patients.Leukemic and T cells were obtained from CLL patients´ peripheral blood, and from the CLL mouse model Eµ-TCL-1. Transwell migration assay was used to evaluate chemotaxis. T cells were activated with plate bound-anti-CD3 mAb. Activation markers were assessed by flow cytometry and cytokines by ELISA. Statistical significance was analyzed with the GraphPad Prism software.We found that CMP (3-30 µM) increased the migration towards S1P of leukemic cells from CLL patients and from the CLL mouse model (p