Life and death of multiple myeloma cells

Multiple myeloma (MM) is a B-cell malignancy in which plasma cells have decreased proliferative ability and an extended lifespan. Zhang and colleagues (page 1885) set out to identify the molecular processes responsible for this extended survival (or delayed apoptosis) in MM cells.

First they showed (using inhibitors of transcription and protein turnover) that survival of MM cells appeared to require the continuous expression of a protein with a high turnover rate. MM cells express a number of survival proteins (of the Bcl-2 family), but changes in levels of one of these, myeloid cell factor–1 (Mcl-1), paralleled changes in cell survival. Thus when Mcl-1 levels were low, the MM cells underwent apoptosis, while levels of Mcl-1 were high in nonapoptotic cells. This correlation by itself was not sufficient to determine whether changes in Mcl-1 levels were actually driving, or merely reflecting, cell death or survival. They then used antisense oligonucleotides or transfection with Mcl-1 cDNA to specifically decrease or increase, respectively, cellular levels of Mcl-1. These approaches confirmed the earlier conclusions: knocking out Mcl-1 levels induced apoptosis and increasing Mcl-1 levels gave the cells even greater resistance to cell death.

Zhang and colleagues show that increased expression of a single survival protein, Mcl-1, may be sufficient to confer the malignant phenotype in MM cells. Apart from providing important new insights into the molecular pathology of MM cells, this work could lead to the development of new therapeutic strategies for the treatment of MM based on the targeted disruption of Mcl-1 expression.