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

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Spliceosome machinery mutations are frequent in myeloid malignancies.
• Targeted therapies for these mutations remain limited.

Purpose of the Study:

• To identify novel therapeutic agents targeting SRSF2-mutant myeloid malignancies.
• To investigate the mechanism of action of identified compounds.

Main Methods:

• Conducted an in vitro high-throughput drug screen using isogenic cell lines.
• Utilized xenograft models with SRSF2-mutated primary human samples.
• Employed transmission electron microscopy and 3D light microscopy.

Main Results:

• Identified RKI-1447, a Rho-associated protein kinase inhibitor, as selectively cytotoxic to SRSF2-mutant cells.
• RKI-1447 induced mitotic catastrophe and severe nuclear deformation in SRSF2-mutant cells.
• Observed microtubule reorganization and nuclear segmentation exacerbated by RKI-1447.

Conclusions:

• SRSF2 mutations lead to nuclear morphology changes driven by microtubule dynamics.
• RKI-1447 targets these nuclear alterations, preventing mitosis completion in mutant cells.
• Findings offer a new therapeutic strategy for pre-leukemic SRSF2-mutant cells.