1 Cell death via DR 5 , but not DR 4 , is regulated by p 53 in myeloma cells

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Myeloma cells are sensitive to TRAIL through the two death receptors DR4 and DR5. Because p53 directly modulates expression of death receptors, we investigated here whether p53 can modulate myeloma sensitivity to TRAIL. We found that TP53 affects the sensitivity of myeloma cells to the DR5 agonistic human antibody lexatumumab, but not the DR4 antibody mapatumumab. TP53 wildtype myeloma cells overexpressed DR5 in correlation with sensitivity to lexatumumab. Both non-genotoxic (nutlin3a) and genotoxic (melphalan) p53 inducing stresses increased DR5 expression only in TP53 wildtype cells and synergistically increased lexatumumab efficiency, yet did not increase DR4 expression nor sensitivity to mapatumumab. Silencing of p53 strongly decreased DR5 expression and induced resistance to nutlin3a and lexatumumab, but did not modulate DR4 expression or sensitivity to mapatumumab. Increase of lexatumumab efficiency induced by nutlin3a was related to a p53-dependent increase of DR5 expression. In primary myeloma cells, nutlin3a increased DR5 expression and lexatumumab efficiency, but did not increase mapatumumab efficiency. Taken together, our findings indicate that p53 controls the sensitivity of myeloma through DR5, but not DR4, and suggest that a subset of patients with multiple myeloma may benefit from DR5 therapy. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.