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Su, Minhua; Fleischer, Tom; Grosheva, Inna; Horev, Melanie Bokstad; Olszewska, Malgorzata; Mattioli, Camilla Ciolli; Barr, Haim; Plotnikov, Alexander; Carvalho, Silvia; Moskovich, Yoni; Minden, Mark D.; Chapal-Ilani, Noa; Wainstein, Alexander; Papapetrou, Eirini P.; Dezorella, Nili; Cheng, Tao; Kaushansky, Nathali; Geiger, Benjamin; Shlush, Liran I.
iScience, 04/2024, Letnik: 27, Številka: 4Journal Article
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 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 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. Display omitted •RKI-1447 identified in high-throughput screening as potent for SRSF2 mutant cells•RKI-1447 effective in xenograft model against primary human leukemia samples•The Inhibitor causes mitotic catastrophe, cytoskeleton reorganization, severe nuclear deformation•The results point to a new therapeutic approach for leukemias involving SRSF2 mutations Molecular biology; Cell biology; Cancer
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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