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

Genome damage is a main driver of malignant transformation, but it also induces aberrant inflammation via the cGAS/STING DNA-sensing pathway. Activation of cGAS/STING can trigger cell death and senescence, thereby potentially eliminating genome-damaged cells and preventing against malignant trans-formation. Here, we report that defective ribonucleotide excision repair (RER) in the hematopoietic system caused genome insta-bility with concomitant activation of the cGAS/STING axis and compromised hematopoietic stem cell function, ultimately resulting in leukemogenesis. Additional inactivation of cGAS, STING, or type I IFN signaling, however, had no detectable effect on blood cell generation and leukemia development in RER- deficient hematopoietic cells. In wild-type mice, hematopoiesis under steady-state conditions and in response to genome damage was not affected by loss of cGAS. Together, these data challenge a role of the cGAS/STING pathway in protecting the hematopoi-etic system against DNA damage and leukemic transformation. Significance: Loss of cGAS/STING signaling does not impact DNA damage-driven leukemogenesis or alter steady-state, per-turbed or malignant hematopoiesis, indicating that the cGAS/ STING axis is not a crucial antioncogenic mechanism in the hematopoietic system. See related commentary by Zierhut, p. 2807