The imbalance between Bim and Mcl‐1 expression controls the survival of human myeloma cells

Abstract

Multiple myeloma is a fatal B cell malignancy characterized by the accumulation of plasma cells within the bone marrow. IL‐6 is a major survival factor for myeloma cells. Bcl‐2 protein family regulates pathways to apoptosis that are activated upon growth factor deprivation. Pro‐apoptotic proteins that have only a single Bcl‐2 homology domain, BH3‐only, are potent inducers of apoptosis. In myeloma cells, Mcl‐1 has been shown to be a major anti‐apoptotic protein that appears to regulate cell survival through the JAK/STAT pathway. In this study, we examined the regulation of the BH3‐only protein Bim and its interaction with Mcl‐1. The three major Bim isoforms are expressed in myeloma cells and are negatively regulated by IL‐6. Blockade of IL‐6 signaling induces an up‐regulation of Bim concomitant to Mcl‐1 down‐regulation. Of major interest, Bim is found strongly associated with Mcl‐1 in viable myeloma cells while this interaction is disrupted under apoptosis induction. Of note, while Bim is also found strongly associated to Bcl‐2, this interaction is not changed under apoptosis induction. Thus, in myeloma cells, Mcl‐1 neutralizes Bim through complex formation and therefore prevents apoptosis. Under apoptosis induction, the disappearance of Mcl‐1 allows Bim to exercise its pro‐apoptotic function and to activate Bax.