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 transformation. Here, we report that defective ribonucleotide excision repair (RER) in the hematopoietic system caused genome instability 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, this data challenges a role of the cGAS/STING pathway in protecting the hematopoietic system against DNA damage and leukemic transformation.