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

Abstract

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 four 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 mice nor human cells. ROCKi induced mitotic catastrophe through their apparent effects on microtubules and nuclear organization. Transmission electron microscopy revealed that SRSF2 mutations induce deep nuclear indentation and segmentation, driven by microtubule-rich cytoplasmic intrusions, which were exacerbated by ROCKi. The severe nuclear deformation driven by the combination of SRSF2 Mut and ROCKi prevent cells from completing mitosis. These findings shed light on new ways to target SRSF2 and on the role of the microtubule system in SRSF2 Mut cells.