A model for bortezomib resistance in MCL. Bortezomib sensitivity is shown as a function of secretory load relative to the capacity of a cell to deal with protein load. Bortezomib-resistant MCL cells progressing in differentiation through the GC acquire a plasmacytic phenotype that increases their capacity to deal with the protein load. In the absence of increased protein synthesis, this confers a survival advantage during proteasome inhibition. In fully differentiated plasma cells, the secretory load increases and sensitizes these cells to bortezomib.