Rock inhibitors target SRSF2 leukemia by disrupting cell mitosis and nuclear morphology

Spliceosome machinery mutations are common early mutations in myeloid malignancies, however effective targeted therapies against them are still lacking. In the current study, we used an in vitro high-throughput drug screen among five different isogenic cell lines and identified ROCK inhibitors (ROCKi) as selective inhibitors of SRSF2 mutants. ROCKi targeted SRSF2-Mut primary human samples in a xenografts model and were not toxic to neither mice nor human cells. ROCKi induced mitotic catastrophe through its effect on microtubules and changes in nuclear shape. On top of that, transmission electron microscope imaging revealed that SRSF2 mutations create nuclear indentation and segmentation that result from microtubule forces. ROCKi exacerbated this phenotype. These results suggest that ROCKi exploits the vulnerabilities of SRSF2 Mut cells. They also expose a phenotype of SRSF2 Mut cells that can be used to target them effectively.