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

CASSARINO CHIARA; BERNATOWIEZ JULIANA; SARAPURA MARTINEZ VALERIA JUDITH; BUONINCONTRO BRENDA; BERTINI MARTIN; BEZARES RAIMUNDO FERNANDO; VERMEULEN MÓNICA; GIORDANO MIRTA; GAMBERALE ROMINA; COLADO ANA; BORGE MERCEDES

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2022

Reunión Anual de Sociedades de Biociencias, Buenos Aires 16-19 Noviembre 2022.

Leukemic B cell proliferation mainly occurs in the lymph nodes in responseto signals provided by the tumor microenvironment, such asCD40L and cytokines secreted by activated T cells. GRK2 regulatesB cell homing to lymph nodes by inducing S1PR1 (Sphingosine-1phosphate receptor-1) downregulation, which allows the lymphocyteto overcome the S1P-mediated retention in the blood, and to followthe chemokine gradient into the tissue. GRK2 also modulates othercellular functions such as activation and survival in different cancercells. We have previously found that a GRK2 inhibitor, CMPD101(CMP) increases leukemic-cell migration to S1P without affectingspontaneous or drug-induced apoptosis. Here we aim to expand thestudy on the effect of GRK2 inhibition in the activation and migrationof leukemic and T cells from CLL patients. Leukemic and T cellswere obtained from CLL patient´s peripheral blood, and from theCLL mouse model Eμ-TCL-1. Transwell migration assay was usedto evaluate chemotaxis. T cells were activated with plate bound-anti-CD3 mAb. Activation markers were assessed by flow cytometry andcytokines by ELISA. Statistical significance was analyzed with theGraphPad Prism software. We found that CMP (3-30 μM) increasedthe migration towards S1P of leukemic cells from CLL patients andalso from the CLL mouse model (p<0.05, n=10), while it did notmodify leukemic cell migration in response to CXCL13, CXCL12 andCCL21. Also, CMP increased T cell migration in response to S1P,while it decreased migration towards CCL21 (p<0.05, n=8). Moreover,CMP decreased CD40L expression and IL-10 and IFNɣ secretionby activated T cells and reduced the expression of the activationmarker CD86 on leukemic cells induced by activated T cells (p<0.05,n=8). Our results suggest that GRK2 inhibition may be useful for: 1)to induce CLL cell mobilization from lymphoid tissues by increasingcell migration towards S1P and 2) to impair CLL cell activation byreducing T cell signaling.