Targeting ULK1 in cancer stem cells: insight from chronic myeloid leukemia.

Minimal residual disease (MRD) refers to a low number of cells that persist anti-cancer treatment and is the major cause of relapse in solid cancers and leukemias. In chronic myeloid leukemia (CML), a paradigm for stem cell-driven cancer, MRD is maintained by tyrosine kinase inhibitor (TKI)-insensitive leukemic stem cells (LSCs), which may rely on fundamental metabolic processes to resist drug treatment. Macroautophagy/autophagy is a cytoprotective process that has been highlighted as critical for sustaining LSC survival during TKI treatment in robust experimental models of CML. Our recent study shows that the autophagy-initiating kinase ULK1 is required for maintaining energy and redox balance in CML LSCs. Pharmacological inhibition of ULK1 results in stress-induced differentiation of LSCs, rendering them sensitive to TKI treatment, uncovering a promising strategy for selective eradication of LSCs in CML patients. CML: chronic myeloid leukemia; LSC: leukemic stem cell; MAPK: mitogen-activated protein kinase; MRD: minimal residual disease; TKI: tyrosine kinase inhibitor.