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 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.
| Original language | English |
|---|---|
| Article number | 109443 |
| Journal | iScience |
| Volume | 27 |
| Issue number | 4 |
| Early online date | 6 Mar 2024 |
| DOIs | |
| Publication status | Published - 19 Apr 2024 |
Bibliographical note
We thank Dr. Ron Rotkopf from the Department of Life sciences Core Facilities, Weizmann Institute of Science, who helped with the statistics. We thank Meital Kupervaser and Corine Katina from the de Botton institute for Protein Profiling of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, who helped with proteomic and phosphoproteomic experiment. Electron microscopy studies were conducted at the Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging at the Weizmann Institute of Science. Some of the images in this paper were acquired at the Advanced Optical Imaging Unit, de Picciotto-Lesser Cell Observatory unit at the Moross Integrated Cancer Center Life Science Core Facilities, Weizmann Institute of Science. The SGC library was supplied by the Structural Genomics Consortium under an Open Science Trust Agreement: https://www.thesgc.org/click-trust. The authors acknowledge the support of the Minerva Center for Aging, from physical materials to human tissues at the Weizmann Institute of Science.This work by the authors was supported through the National Natural Science Foundation of China (81861148029), Ministry of Science and Technology of China (2020YFE0203000, 2021YFA1100900), the National Natural Science Foundation of China (92368202), the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2021-I2M-1-040), the Fundamental Research Funds for the Central Universities (3332021093), the EU Horizon 2020 grant project MAMLE ID 714731, LLS and the Rising Tide Foundation grant ID RTF6005-19, ISF-NSFC 2427/18, ISF-IPMP-Israel Precision Medicine Program 3165/19, ISF 1123/21, BIRAX 713023, and the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, awarded to L.I.S. L.I.S. is an incumbent of the Ruth and Louis Leland career development chair. N.K. is an incumbent of the Applebaum Foundation Research Fellow Chair. This research was also supported by the Sagol Institute for Longevity Research, the Barry and Eleanore Reznik Family Cancer Research Fund, Steven B. Rubenstein Research Fund for Leukemia and Other Blood Disorders, the Swiss Society Institute for Cancer Prevention Research at the Weizmann Institute of Science, and the Applebaum Foundation. Work in the Papapetrou lab was supported by the US National Institutes of Health (NIH) grants R01HL137219 and R01CA225231, the Leukemia & Lymphoma Society, and the Edward P. Evans Foundation.
Publisher Copyright:
© 2024 The Author(s)
All Science Journal Classification (ASJC) codes
- General