Engineering the Allogeneic Stem Cell Graft for AML Immunotherapy: From Transplant Protection to Therapeutic Redistribution

The inability to restrict acute myeloid leukemia immunotherapy to leukemic cells without damaging normal hematopoiesis remains a central challenge. Graft engineering addresses this limitation by modifying donor hematopoietic stem and progenitor cells so that the reconstituting hematopoietic system becomes resistant to a selected immunotherapy while residual leukemia remains susceptible. I examine the molecular principles, target-specific constraints, pharmacological consequences, and translational implications of this strategy across five validated immunotargets: CD33, CD123, FLT3, KIT, and CD45. These targets span a spectrum from dispensable lineage antigens to essential signaling receptors and pan-hematopoietic conditioning targets, requiring either antigen deletion or function-preserving epitope substitution. Beyond preventing hematopoietic toxicity, graft engineering redistributes therapeutic engagement by remodeling normal antigen-expressing hematopoiesis, thereby influencing the efficacy and toxicity of antibody- and chimeric antigen receptor–based therapies. I outline a translational path from single-edited grafts toward multiplex platforms designed to improve disease control while limiting antigen escape.