Selective targeting in leukemic stem cells through modulation of selenoprotein biosynthesis by PSTK

Modulating metabolic pathways emerges as a promising therapeutic approach, particularly post-chemotherapy relapse. Phenotypic CRISPR-Cas9 screening identified phosphoseryl-tRNA kinase (PSTK), an atypical enzyme in the selenoprotein biosynthesis, as an AML differentiation blocker and a broad anti-cancer target.

In vivo study demonstrated PSTK’s indispensable role in sustaining leukemic stem cell self-renewal and initiating of leukemia. Pharmacologic PSTK inhibition effectively targeted chemo-resistant AML in mice and patient-derived xenograft (PDX) models, with a discernible preference for malignant cell over normal blood cells. Mechanistically, PSTK inhibition induced reactive oxygen species (ROS)-mediated oxidative stress, mitochondrial damage and eventual engagement of the cGAS-STING pathway and ROS regulation loop, culminating in ferroptosis.