The therapeutic administration of chimeric antigen receptor (CAR)-based cell therapies has considerably advanced the treatment of certain cancers. Unfortunately, the successes of CAR-based cell therapies have not yet translated to treatment of acute myeloid leukemia (AML), likely due to the lack of a suitable lineage antigen target. Due to their nonrestrictive expression, most AML antigens are also expressed on hematopoietic stem cells (HSCs), and thus on-target/off-tumor effects of the therapy may lead to the ablation of hematopoietic stem/progenitor cells, causing significant and life-threatening myelotoxicity and prolonged cytopenia. While there are currently dozens of clinical trials underway for various CAR-based therapies in AML patients, no treatment has yet demonstrated the ability to curb on-target/off-tumor killing of healthy HSCs.