Le rôle du complexe Mcl-1/Bim dans la régulation de l'apoptose des cellules de myélome multiple

Multiple myeloma is a plasma cell malignancy. IL-6 is essential for survival of myeloma cells, it up-regulates Mcl-1. Mcl-1 has a major role in myeloma cell survival. The pro-apoptotic protein Bim has an important role as an initiator of apoptosis. We show that the three Bim isoforms are expressed on myeloma cells as well as on B cells. They are endogenously associated to Mcl-1 and Bcl-2. Bim is preferentially co-localised in mitochondria along with the anti-apoptotic counterparts. They neutralise Bim since there is no free Bim. IL-6 starvation induces apoptosis associated to the simultaneous Bim up-regulation and Mcl-1 diminution. Upon apoptosis induction Bim/Bcl-2 complex is not modified whereas Bim/Mcl-1 complex is nearly abolished leading to Bim release and to Bax activation. Mcl-1L and BimEL are cleaved by caspases giving rise to pro-apototic fragments that contribute to the apoptosis amplification loop. Indeed, Bim/Mcl-1 complex is essential for apoptosis regulation of those cells.