Vulnerability of SRSF2 mutated chronic myelomonocytic leukemia to perturbation of cGAS-STING pathway Open Access

• SRSF2P95H promotes leukemia by inducing inflammation and immune activation via activation of the cGAS-STING pathway.

• Targeting R-loop formation and the cGAS-STING axis attenuates leukemogenesis linked to SRSF2 mutations in zebrafish and human HSPCs.

Chronic myelomonocytic leukemia (CMML) is characterised by monocytosis in blood and bone marrow and natural progression to acute myeloid leukemia (AML) in up to 30% of patients. The mutation landscape of CMML has been reported, and animal models that recapitulate its clinicopathologic features and progression are needed. We report a CMML zebrafish model based on transgenic SRSF2P95H expression that closely resembled the human disease. Hematological assessment of the transgenic animals showed myelodysplasia, monocytosis, and leukemia 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 leukemia phenotype. The inflammatory effects and their response to treatment were recapitulated in human hematopoietic stem and progenitor cells (HSPC). Collectively, our findings showed a pathogenetic link between SRSF2P95H and cGAS-STING activation in CMML and its vulnerability to therapeutic intervention.