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

Author:

Dressel Nicole1ORCID,Natusch Loreen1ORCID,Munz Clara M.1ORCID,Costas Ramon Santiago1ORCID,Morcos Mina N.F.1ORCID,Loff Anja1ORCID,Hiller Björn1ORCID,Haase Christa1ORCID,Schulze Livia1ORCID,Müller Patrick2ORCID,Lesche Mathias3ORCID,Dahl Andreas3ORCID,Luksch Hella4ORCID,Rösen-Wolff Angela4ORCID,Roers Axel15ORCID,Behrendt Rayk12ORCID,Gerbaulet Alexander1ORCID

Affiliation:

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

2. 2Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.

3. 3DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany.

4. 4Department of Pediatrics, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.

5. 5Institute for Immunology, Heidelberg University Hospital, Heidelberg, Germany.

Abstract

Abstract 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, these data challenge a role of the cGAS/STING pathway in protecting the hematopoietic system against DNA damage and leukemic transformation. Significance: Loss of cGAS/STING signaling does not impact DNA damage–driven leukemogenesis or alter steady-state, perturbed 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

Funder

Fritz Thyssen Stiftung

Deutsche Forschungsgemeinschaft

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Reference74 articles.

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