A model of the role of Atg7 in the regulation of autophagy and apoptosis in AML cells. Initiation of autophagy is regulated by the AMPK/mTOR axis and activation of the ULK1 (UNC-51-like kinase 1) complex and release of the Beclin1-VPS-34 complex from Bcl-2 family members. This allows sequestration of cytosolic proteins into a maturing autophagosome, which is mediated in part by the actions of the E1-like enzyme Atg7, which acts through 2 pathways: conjugation of Atg5 and Atg12 and addition of phosphatidylethanolamine (PE) moieties to LC3. These events are critical for autophagosome elongation and set the stage for lysosomal fusion to form the autolysosome, leading to digestion of cellular contents. Blocking the latter events (eg, by knocking down Atg7) disrupts autophagy and significantly attenuates the cytoprotective actions of this process in AML cells exposed to genotoxic agents such as Ara-C and idarubicin. Atg7 knockdown also acts indirectly by inhibiting stromal cell cytoprotective actions toward AML cells. In this way, Atg7 knockdown can recapitulate the actions of agents such as CQ which disrupt autophagy at a distal point (eg, lysosome acidification). Note that despite its presumed cytoprotective actions, autophagy may under some circumstances promote apoptosis (hatched arrow, bottom), arguing that interfering with this process can potentially act as a double-edged sword. Professional illustration by Patrick Lane, ScEYEnce Studios.