Somatic gene mutations expose cytoplasmic DNA to co-opt the cGAS/STING/NLRP3 axis in myelodysplastic syndromes

Area of Science:

• Hematology
• Molecular Biology
• Immunology

Background:

• Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and inflammation.
• NLRP3 inflammasome and IFN-stimulated gene (ISG) induction are key drivers of MDS pathology.
• Somatic gene mutations affecting splicing and epigenetic regulation are implicated in MDS pathogenesis.

Purpose of the Study:

• To elucidate the mechanisms linking gene mutations to inflammasome activation and myeloid skewing in MDS.
• To identify the signaling pathways involved in driving inflammation and ineffective hematopoiesis in MDS.

Main Methods:

• Utilized immortalized murine hematopoietic stem and progenitor cells with MDS-associated mutations.
• Analyzed primary MDS bone marrow specimens.
• Investigated the role of cyclic GMP-AMP synthase (cGAS) and its downstream signaling pathways.
• Assessed the impact of inhibiting RNA polymerase III and cGAS.

Main Results:

• Accumulation of unresolved R-loops and micronuclei correlated with cGAS activation in MDS cells.
• cGAS/STING signaling led to ISG induction, NLRP3 inflammasome activation, and caspase-1 maturation.
• Inhibition of RNA polymerase III reduced R-loop formation and dampened ISG/inflammasome responses.
• Caspase-1 degraded GATA binding protein 1, causing anemia and myeloid bias, which was reversed by cGAS inhibition.

Conclusions:

• Identified a novel mechanism where distinct MDS-associated mutations converge on the cGAS/STING/NLRP3 axis.
• This pathway drives ISG induction, pyroptosis, and myeloid lineage skewing in MDS.
• Targeting the cGAS pathway offers a potential therapeutic strategy for MDS.