Abstract
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 – so called “Proteostasis” – in drug resistance and relapse.
We tested a range of proteostatic targeting agents against primary, poor risk, AML patient samples and demonstrate a selective vulnerability of both AML blasts and LSCs to inhibition of CKS1-dependent protein degradation in vitro and in vivo using a small molecule inhibitor. Mechanistically, inhibition of CKS1 leads to hyperactivation of RAC1, increased NADPH production and critical levels of intracellular ROS, resulting in death of LSCs.
Conversely, CKS1 inhibition has the opposite effect on healthy haematopoiesis. Healthy haematopoietic stem and progenitor cells (HSPCs) display increased quiescence upon inhibition of CKS1, a phenotype which confers chemoprotection of healthy HSPCs during clinical chemotherapy protocols (Cytarabine + Doxorubicin, 5+3). A phenotype conserved by intestinal stem and progenitor cells.
Together these findings demonstrate a key vulnerability of AML-LSCs to CKS1-inhibition, while it preserves healthy stem cells. This offers the prospect of both depleting LSCs in vivo and bringing back clinically unfit patients into the pool for intensive chemotherapeutic treatment.