Defective erythropoiesis in MM.

Hypothetical model of the pathogenic defective maturation of erythroid cells by malignant cytotoxic plasma cells in active MM. GpA^+dim erythroblasts progress to the GpA^+bright form by GATA-1. At their prebasophilic/basophilic stage (GpA^+dim), erythroblasts are highly susceptible to Fas stimulation because they can be negatively regulated by Fas-L from mature (GpA^+bright) erythroblasts just as GpA^+interm erythroblasts are restrained by TRAIL. Fas and the TRAIL receptors, namely, DR4/DR5 molecules, are expressed during erythroid differentiation, though they are not functional in specific stages (empty symbols). Highly malignant myeloma cells express large amounts of both Fas-L and TRAIL and exert a direct erythroblast cytotoxicity by inducing apoptosis. The cytotoxic mechanism operates during either the immature or the semimature stage of differentiation by both Fas and DR4/DR5. The cytoplasmic caspases activated by these apoptogen receptors induce the cleavage of GATA-1, whose intracellular defect promotes an arrest in the maturative progression. This results in a relative increase of immature erythroblasts and systematic impairment of the erythroid matrix.