Clearance of genome-damaged cells from the hematopoietic system via p53 without contribution by the cGAS/STING axis

Abstract

Cell-intrinsic response patterns control risks arising from genome-damage, preventing malignant transformation. The DNA sensor cyclic-GMP-AMP synthase (cGAS) has emerged as a new principle detecting genome damage, as it can be triggered by aberrant self-DNA. Stimulator of interferon genes (STING)-activation downstream of cGAS can drive cells into senescence or cell death and induces antiproliferative type I interferon (IFN) and pro-apoptotic tumor necrosis factor responses. Herein, we investigated how DNA damage-driven activation of cGAS/STING signaling impacts on hematopoiesis. Defective ribonucleotide excision repair (RER) in the hematopoietic system caused chromosomal instability as well as robust activation of the cGAS/STING/IFN axis, and compromised hematopoietic stem cell function, resulting in cytopenia and ultimately leukemia. Whereas loss of p53 largely rescued RER-deficient hematopoiesis at the cost of further accelerated leukemogenesis, the additional inactivation of cGAS, STING or type I IFN signaling had no detectable effect on blood cell generation and leukemia development. Moreover, cGAS-deficient hematopoiesis showed unaltered responses to spontaneous or acute DNA damage. Our data demonstrate that the cGAS/STING pathway is dispensable for the hematopoietic system coping with chronic or acute DNA damage and does not protect against leukemic transformation in the absence of RER.