@article { , title = {SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4}, 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.}, doi = {10.1038/s41467-018-07620-0}, eissn = {2041-1723}, issue = {1}, journal = {Nature Communications}, publicationstatus = {Published}, publisher = {Nature Publishing Group}, url = {https://nottingham-repository.worktribe.com/output/1476307}, volume = {9}, keyword = {General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry}, year = {2018}, author = {Tzelepis, Konstantinos and De Braekeleer, Etienne and Aspris, Demetrios and Barbieri, Isaia and Vijayabaskar, M. S. and Liu, Wen-Hsin and Gozdecka, Malgorzata and Metzakopian, Emmanouil and Toop, Hamish D. and Dudek, Monika and Robson, Samuel C. and Hermida-Prado, Francisco and Yang, Yu Hsuen and Babaei-Jadidi, Roya and Garyfallos, Dimitrios A. and Ponstingl, Hannes and Dias, Joao M. L. and Gallipoli, Paolo and Seiler, Michael and Buonamici, Silvia and Vick, Binje and Bannister, Andrew J. and Rad, Roland and Prinjha, Rab K. and Marioni, John C. and Huntly, Brian and Batson, Jennifer and Morris, Jonathan C. and Pina, Cristina and Bradley, Allan and Jeremias, Irmela and Bates, David O. and Yusa, Kosuke and Kouzarides, Tony and Vassiliou, George S.} }