CKS1 inhibition reveals vulnerabilities in leukemic stem cells with concomitant protection of healthy hematopoietic stem cells

Acute myeloid leukemia (AML) is an aggressive hematological disorder comprising a hierarchy of quiescent leukemic stem cells (LSCs) and proliferating blasts with limited self-renewal ability. AML has a dismal prognosis, with extremely low two-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols to deplete LSCs, and the significant toxicity towards healthy hematopoietic cells. Whilst much work has been done to identify genetic and epigenetic vulnerabilities in AML LSCs, little is known about protein homeostasis in drug resistance and relapse. By targeting the proteostatic regulator CKS1, we demonstrate a dual role for CKS1-dependent protein degradation in reducing AML blasts in vivo, and importantly depleting LSCs, whilst inhibition of CKS1 has the opposite effect on normal hematopoiesis, protecting normal hematopoietic stem cells from chemotherapeutic toxicity. Together these findings demonstrate CKS1-dependent proteostasis is a key vulnerability in malignant stem cell biology.