DNA polymerase θ protects leukemia cells from metabolically induced DNA damage

Area of Science:

• Molecular Biology
• Cancer Biology
• DNA Repair

Background:

• Leukemia cells accumulate DNA damage but possess altered DNA repair to evade apoptosis.
• Formaldehyde from serine/1-carbon metabolism creates toxic DNA-protein crosslinks (DPCs) in leukemia cells, particularly those with oncogenic tyrosine kinases (OTKs).

Purpose of the Study:

• To investigate the role of DNA polymerase theta (POLθ) in repairing formaldehyde-induced DNA damage in leukemia cells.
• To evaluate POLθ as a therapeutic target in leukemia, especially in OTK-driven cancers.

Main Methods:

• Analysis of DPC accumulation and POLθ expression in leukemia cells with specific OTKs (FLT3-ITD, JAK2-V617F, BCR-ABL1).
• Investigated the mechanism of POLθ upregulation via ERK1/2 signaling and c-CBL E3 ligase.
• Assessed the impact of POLθ deficiency (Polq-/-) on leukemia development in murine bone marrow cells.
• Evaluated the efficacy of genetic and pharmacological targeting of POLθ activities (polymerase and helicase).
• Tested combination therapies involving OTK inhibitors, etoposide, and POLθ inhibitors in vitro and in vivo.

Main Results:

• OTKs enhance POLθ expression to repair DPCs, protecting leukemia cells.
• POLθ deficiency abrogates the transforming activity of oncogenes in leukemia.
• Targeting POLθ's polymerase and helicase activities shows therapeutic potential.
• Combination therapies enhance anti-leukemia effects.

Conclusions:

• POLθ is crucial for leukemia cell survival by repairing formaldehyde-induced DNA lesions.
• Targeting POLθ represents a viable therapeutic strategy for leukemia, particularly OTK-driven types.