Activation of the cGAS/STING Axis in Genome-Damaged Hematopoietic Cells Does Not Impact Blood Cell Formation or Leukemogenesis
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
Abstract
UNLABELLED: 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.
Details
Original language | English |
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Pages (from-to) | 2858-2872 |
Number of pages | 15 |
Journal | Cancer research |
Volume | 83 |
Issue number | 17 |
Publication status | Published - 1 Sept 2023 |
Peer-reviewed | Yes |
External IDs
PubMed | 37335136 |
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ORCID | /0000-0002-3274-7163/work/142249715 |
Keywords
Research priority areas of TU Dresden
DFG Classification of Subject Areas according to Review Boards
Subject groups, research areas, subject areas according to Destatis
Sustainable Development Goals
ASJC Scopus subject areas
Keywords
- Animals, Mice, Hematopoiesis/genetics, Interferon Type I/metabolism, Leukemia/genetics, Nucleotidyltransferases/genetics, Signal Transduction