CD44 regulates the apoptotic response and promotes disease development in chronic lymphocytic leukemia
Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels la glycoprotéine de surface cellulaire CD44 favorise le développement d'une leucémie lymphocytaire chronique
The cell-surface glycoprotein CD44 is expressed in chronic lymphocytic leukemia (CLL), but its functional role in this disease is poorly characterized. We therefore investigated the contribution of CD44 to CLL in a murine disease model, the Eμ-TCL1 transgenic mouse, and in CLL patients. Surface CD44 increased during murine CLL development. CD44 ex-pression in human CLL was induced by stimulation with IL4/CD40L and by stroma cell contact. Engagement of CD44 by its natural ligands, hyaluronic acid or chondroitin sulfate, protected CLL cells from apoptosis, while anti-CD44 siRNAs impaired tumor cell viability. Deletion of CD44 during TCL1-driven murine leukemogenesis reduced the tumor burden in peripheral blood and spleen and led to a prolonged overall survival. The leukemic cells from these CD44 knock-out animals revealed lower levels of anti-apoptotic MCL1, a higher propensity to apoptosis, and a diminished B-cell receptor kinase response. The inhibitory anti-CD44 antibodies IM7 and A3D8 impaired the viability of CLL cells in suspension cultures, in stroma contact models, and in vivo, via MCL1 reduction and by effector caspase activation. Taken together, CD44 expression in CLL is mediated by the tumor microenvironment. As a co-receptor CD44 promotes leukemogenesis by regulating stimuli of MCL1 expression. Moreover, CD44 can be addressed therapeutically in CLL by specific antibodies.