question: The transmembrane metalloprotease aminopeptidase‐N (APN)/CD13 is overexpressed in various solid and hematological malignancies in humans, including acute myeloid leukemia (AML) and is thought to influence tumor progression. Here, we investigated the contribution of APN/CD13 to the regulation of growth and survival processes in AML cells in vitro. Anti‐CD13 monoclonal antibodies MY7 and SJ1D1 (which do not inhibit APN activity) and WM15 (an APN‐blocking antibody) inhibited the growth of the AML cell line U937 and induced apoptosis, as evidenced by cell accumulation in the sub‐G(1) phase, DNA fragmentation, and phosphatidylserine externalization. Isotype‐matched IgG1 and the APN/CD13 enzymatic inhibitors bestatin and 2' ,3‐dinitroflavone‐8‐acetic acid, were ineffective. Internalization of CD13‐MY7 complex into cells was followed by mitochondrial membrane depolarization, Bcl‐2 and Mcl‐1 down‐regulation, Bax up‐regulation, caspase‐9, caspase‐8, and caspase‐3 activation, and cleavage of the caspase substrate PARP‐1. The broad‐spectrum caspase inhibitor Z‐VAD‐fmk and the caspase‐9‐ and caspase‐8‐specific inhibitors significantly attenuated apoptosis. CD13 ligation also induced apoptosis and PARP‐1 cleavage in primary AML blasts, whereas normal blood cells were not affected. Overall, these data provide new evidence that CD13 can serve as a target for inducing caspase‐dependent apoptosis in AML (independently of its APN activity). These findings may have implications for tumor biology and treatment.—Piedfer, M., Dauzonne, D., Tang, R., N'Guyen, J., Billard, C., Bauvois, B. Aminopeptidase‐N/CD13 is a potential proapoptotic target in human myeloid tumor cells. FASEB J. 25, 2831‐2842 (2011). http://www.fasebj.org