Interestingly, the SASH1-Sam1 Y652A mutation inhibits the formation of the SASH1-Sam1/EphA8-Sam complex, whereas the leukemia-linked mutation G978D in EphA8-Sam highly reduces the binding affinity for SASH1-Sam1 by interfering with the network of interactions engaging the key G978 residue. Here, SASH1 is linked to leukemia.