Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia

Abstract

B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remissionrates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated withadverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1is an inhibitor of vacuolar H+-ATPase that is frequently used at high concentration to block late-phase autophagy.Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killedpediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathwayby activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as wellas by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatricpatients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targetedleukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe.Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acutelymphoblastic leukemia.