SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4

Tzelepis, Konstantinos; De Braekeleer, Etienne; Aspris, Demetrios; Barbieri, Isaia; Vijayabaskar, M. S.; Liu, Wen-Hsin; Gozdecka, Malgorzata; Metzakopian, Emmanouil; Toop, Hamish D.; Dudek, Monika; Robson, Samuel C.; Hermida-Prado, Francisco; Yang, Yu Hsuen; Babaei-Jadidi, Roya; Garyfallos, Dimitrios A.; Ponstingl, Hannes; Dias, Joao M. L.; Gallipoli, Paolo; Seiler, Michael; Buonamici, Silvia; Vick, Binje; Bannister, Andrew J.; Rad, Roland; Prinjha, Rab K.; Marioni, John C.; Huntly, Brian; Batson, Jennifer; Morris, Jonathan C.; Pina, Cristina; Bradley, Allan; Jeremias, Irmela; Bates, David O.; Yusa, Kosuke; Kouzarides, Tony; Vassiliou, George S.

Abstract

We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.

Citation

Tzelepis, K., De Braekeleer, E., Aspris, D., Barbieri, I., Vijayabaskar, M. S., Liu, W.-H., Gozdecka, M., Metzakopian, E., Toop, H. D., Dudek, M., Robson, S. C., Hermida-Prado, F., Yang, Y. H., Babaei-Jadidi, R., Garyfallos, D. A., Ponstingl, H., Dias, J. M. L., Gallipoli, P., Seiler, M., Buonamici, S., …Vassiliou, G. S. (2018). SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4. Nature Communications, 9(1), Article 5378. https://doi.org/10.1038/s41467-018-07620-0

• Journal Article Type: Article
• Acceptance Date: Nov 9, 2018
• Online Publication Date: Dec 19, 2018
• Publication Date: 2018-12
• Deposit Date: May 20, 2019
• Publicly Available Date: May 21, 2019
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 1
• Article Number: 5378
• DOI: https://doi.org/10.1038/s41467-018-07620-0
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/1476307
• Publisher URL: https://www.nature.com/articles/s41467-018-07620-0
• Contract Date: May 21, 2019