TY - JOUR
T1 - The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia
AU - de Rooij, Martin F. M.
AU - Kuil, Annemieke
AU - Geest, Christian R.
AU - Eldering, Eric
AU - Chang, Betty Y.
AU - Buggy, Joseph J.
AU - Pals, Steven T.
AU - Spaargaren, Marcel
PY - 2012
Y1 - 2012
N2 - Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton tyrosine kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin alpha(4)beta(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLLcells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth-and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression. (Blood. 2012;119(11):2590-2594)
AB - Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton tyrosine kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin alpha(4)beta(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLLcells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth-and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression. (Blood. 2012;119(11):2590-2594)
U2 - https://doi.org/10.1182/blood-2011-11-390989
DO - https://doi.org/10.1182/blood-2011-11-390989
M3 - Article
C2 - 22279054
SN - 0006-4971
VL - 119
SP - 2590
EP - 2594
JO - Blood
JF - Blood
IS - 11
ER -