In this study, we demonstrate that CKS1 is a key protein in this paradigm, with LSCs expressing higher CKS1 than most AML blasts, providing a selective vulnerability of LSCs to inhibition of the SCFSKP2-CKS1 E3 ubiquitin ligase complex, while sparing normal HSCs from chemotherapeutic toxicity. This evidence concerns the gene CKS1B and acute myeloid leukemia.