PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Acute myeloid leukemia (AML) exhibits differentiation arrest and relies on oxidative metabolism.
• Genetic diversity in AML shares common features.
• Leukemic stem cells are critical for AML persistence and relapse.

Purpose of the Study:

• Identify novel therapeutic targets in AML.
• Investigate the role of phosphoseryl-transfer RNA kinase (PSTK) in AML.
• Develop strategies to overcome chemotherapy resistance in AML.

Main Methods:

• Phenotypic CRISPR-CRISPR-associated protein 9 (CRISPR-Cas9) screening in AML cells.
• Pharmacologic inhibition of PSTK (PSTKi) in vitro and in vivo.
• Murine and patient-derived xenograft models of AML.
• Analysis of reactive oxygen species (ROS), mitochondrial DNA release, and cGAS-STING pathway activation.
• Assessment of iron metabolism and ferroptosis induction.

Main Results:

• CRISPR-Cas9 screen identified PSTK as essential for AML.
• PSTK inhibition impaired AML cell growth and leukemic stem cell self-renewal.
• Timed PSTKi effectively targeted chemotherapy-resistant AML in vivo with selectivity for malignant cells.
• PSTKi induced ROS, mitochondrial DNA release, and cGAS-STING activation, disrupting iron metabolism and augmenting ferroptosis.
• A self-reinforcing PSTK-cGAS-STING-ROS loop was identified, leading to oxidative crisis and ferroptotic death of leukemic stem cells.

Conclusions:

• PSTK is a critical target in AML, essential for selenoprotein biosynthesis.
• Targeting PSTK induces a lethal oxidative crisis and ferroptosis in AML stem cells.
• Timed PSTKi offers a potential strategy to enhance chemotherapy by eliminating residual disease and preventing relapse.