Figure 5.

Targeting the CLL/MSC crosstalk using CXCR4/CXCL12 and BCR signaling inhibitors. Several therapeutic strategies have been proposed to inhibit CLL/MSC interactions. (a) blocking of CXCR4 using AMD3100 (71) or using a CXCR4 antibody (148); (b) blocking CXCL12 using NOX-A12 (150); (c) CXCR4/CXCL12 and BCR pathways are interconnected, another way to interfere is to target BCR pathway using different inhibitors: ibrutinib that inhibits BTK and downstream events such as MAPK, PI3K, or NF-κB activation (151) but also reduces VLA-4 activation induced by CXCL12 binding (109) and cell adhesion (79). Acalabrutinib (155) that similarly acts on the migration, the homing and the mobilization of leukemic cells in the circulation. Idelalisib or duvelisib also reduced the ability of stromal cells to support CLL migration and adhesion (161); (d) finally, targeting the over-expression of BCL2 partially induced by the microenvironment has also been proposed (163, 164). Figure created with BioRender.com.