AFF1 and acute lymphoblastic leukemia: In this study, we demonstrate that KMT2A::AFF1 expressing ALL cells are sensitive to M3258 in vitro and in vivo, that treatment with Btz and IPIs activate proteotoxic stress pathways, and that blocking protein synthesis dramatically desensitizes KMT2A::AFF1 ALL cells to PIs- and IPIs- induced apoptosis.