Vulnerability of SRSF2 mutated chronic myelomonocytic leukaemia to perturbation of cGAS-STING pathway

Chronic myelomonocytic leukaemia (CMML) is characterised by monocytosis in blood and bone marrow with 30% progress to acute myeloid leukaemia (AML). The mutation landscape of CMML has been reported, and animal models that recapitulate its clinicopathologic features and progression are needed. We reported a CMML zebrafish model based on transgenic SRSF2P95H expression that closely resembled the human disease. Haematological assessment of the transgenic animals showed myelodysplasia, monocytosis, and leukaemia transformation. Transcriptomic analysis confirmed global splicing alterations and identified inflammatory phenotypes associated with activation of the cGAS-STING pathway. DNA damage, R-loop and dsDNA accumulation were evident. Inhibition of R-loop formation or cGAS-STING axis significantly reduced gene expression associated with inflammation and immune activation and mitigated the leukaemia phenotype. The inflammatory effects and their response to treatment were recapitulated in human HPSC. Collectively, our findings showed a pathogenetic link between SRSF2P95H and cGAS-STING activation in CMML and its vulnerability to therapeutic intervention.