Selective targeting in leukemic stem cells through modulation of selenoprotein biosynthesis by PSTK [RNA-Seq]

Despite the genetic heterogeneity in acute myeloid leukemia (AML), a common feature is the arrest of leukemic myeloblasts at an immature, self-renewing stage, with distinct metabolic processes, rendering them susceptible to oxidative stress compared to normal hematopoietic cells. 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. These findings highlight the dependency of leukemia cells to selenoprotein biosynthesis pathway and advocate for PSTK modulation as a precise and timed therapeutic strategy for AML, preserving hematopoietic stem cell (HSC) functionality.