Based on data presented herein, we propose a model for metformin-induced cell death in ALL cells via ER stress/UPR-mediated apoptosis in which metformin, by decreasing the ATP/AMP ratio promotes i) ATP depletion and unfolded protein accumulation in the ER lumen resulting in proteotoxic and ER stress, and ii) AMPK activation which leads to suppression of the UPR (down-regulation of GRP78), leading to UPR-mediated apoptotic cell death (Figure 6). This evidence concerns the gene HSPA5 and acute lymphoblastic leukemia.