Targeting SRSF2 mutations in leukemia with RKI-1447: A strategy to impair cellular division and nuclear structure

Targeting SRSF2 mutations in leukemia with RKI-1447: A strategy to impair cellular division and nuclear structure

Blog Article

Summary: Spliceosome machinery mutations are common early mutations in myeloid malignancies; however, effective moen rothbury faucet 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 RKI-1447, a Rho-associated protein kinase inhibitor, as selective cytotoxic effector of SRSF2 mutant cells.RKI-1447 targeted SRSF2 mutated primary human samples in xenografts models.RKI-1447 induced mitotic catastrophe and induced major reorganization of the microtubule system and milwaukee 49-22-5603 severe nuclear deformation.Transmission electron microscopy and 3D light microscopy revealed that SRSF2 mutations induce deep nuclear indentation and segmentation that are apparently driven by microtubule-rich cytoplasmic intrusions, which are exacerbated by RKI-1447.

The severe nuclear deformation in RKI-1447-treated SRSF2 mutant cells prevents cells from completing mitosis.These findings shed new light on the interplay between microtubules and the nucleus and offers new ways for targeting pre-leukemic SRSF2 mutant cells.