CD9, a key actor in the dissemination of lymphoblastic leukemia, modulating CXCR4-mediated migration via RAC1 signaling
Menée à l'aide de modèles murins, cette étude française met en évidence des mécanismes par lesquels, via l'activation de la signalisation RAC1, la tétraspanine CD9 favorise la dissémination des cellules de leucémie lymphoblastique aiguë B
CD9 expression enhances the CXCL12-induced migration of pre-B leukemic lymphocytes via RAC1 signaling.CD9 influences the chemotactic migration and engraftment of pre-B leukemic cells in NOD/SCID mouse testis. CD9, a member of the tetraspanin family, has been implicated in hematopoietic and leukemic stem cell homing. We investigated the role of CD9 in the dissemination of B acute lymphoblastic leukemia (B-ALL) cells, by stably downregulating CD9 in REH and NALM6 cells. CD9 expression was associated with higher levels of REH cell adhesion to fibronectin and CXCR4-mediated migration. Death occurred later in NOD/SCID mice receiving for transplantation REH cells depleted of CD9 than in mice receiving control cells. After CXCL12 stimulation, CD9 promoted the formation of long cytoplasmic actin-rich protrusions. We demonstrated that CD9 enhanced RAC1 activation, in both REH cells and blasts from patients. Conversely, the overexpression of a competing CD9 C-terminal tail peptide in REH cytoplasm decreased RAC1 activation and cytoplasmic extension formation in response to CXCL12. Finally, the inhibition of RAC1 activation decreased migration in vitro, and the depletion of RAC1 protein from transplanted REH cells increased mouse survival. Furthermore, a testis-conditioned medium induced the migration of REH and NALM6 cells, and this migration was impeded by an anti-CD9 antibody. The level of CD9 expression also influenced the homing of these cells in mouse testes. These findings demonstrate, for the first time, that CD9 plays a key role in the CXCR4-mediated migration and engraftment of B-ALL cells in the bone marrow or testis, through RAC1 activation.