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Activation of the cGAS/STING Axis in Genome-Damaged Hematopoietic Cells Does Not Impact Blood Cell Formation or

Nicole Dressel1, Loreen Natusch1, Clara M Munz1

  • 1Institute for Immunology, Faculty of Medicine, TU Dresden, Dresden, Germany.

Cancer Research
|June 19, 2023
PubMed

Insights

Defective DNA repair causes genome instability and leukemia, but the cGAS/STING pathway does not prevent this process in hematopoietic stem cells. This challenges its role in protecting against DNA damage and cancer.

Area of Science:

  • Immunology
  • Genetics
  • Oncology

Background:

  • Genome damage drives cancer and inflammation via the cGAS/STING pathway.
  • cGAS/STING activation can eliminate damaged cells through cell death and senescence.

Purpose of the Study:

  • To investigate the role of the cGAS/STING pathway in DNA damage-induced leukemogenesis.
  • To determine if cGAS/STING signaling protects the hematopoietic system against genome instability.

Main Methods:

  • Studied mice with defective ribonucleotide excision repair (RER) in hematopoietic cells.
  • Analyzed genome instability, cGAS/STING activation, and hematopoietic stem cell function.
  • Assessed leukemogenesis in RER-deficient mice with or without cGAS/STING pathway components.

Main Results:

  • Defective RER caused genome instability, cGAS/STING activation, and compromised hematopoietic stem cells, leading to leukemia.
  • Inactivating cGAS, STING, or type I IFN signaling did not affect blood cell generation or leukemia development in RER-deficient mice.
  • Loss of cGAS did not impact hematopoiesis in wild-type mice under normal or DNA-damaged conditions.

Conclusions:

  • The cGAS/STING pathway does not play a protective role against DNA damage-induced leukemogenesis in the hematopoietic system.
  • The cGAS/STING axis is not a critical antioncogenic mechanism in hematopoiesis.

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