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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.

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Authors

Konstantinos Tzelepis

Etienne De Braekeleer

Demetrios Aspris

Isaia Barbieri

M. S. Vijayabaskar

Wen-Hsin Liu

Malgorzata Gozdecka

Emmanouil Metzakopian

Hamish D. Toop

Monika Dudek

Samuel C. Robson

Francisco Hermida-Prado

Yu Hsuen Yang

Dimitrios A. Garyfallos

Hannes Ponstingl

Joao M. L. Dias

Paolo Gallipoli

Michael Seiler

Silvia Buonamici

Binje Vick

Andrew J. Bannister

Roland Rad

Rab K. Prinjha

John C. Marioni

Brian Huntly

Jennifer Batson

Jonathan C. Morris

Cristina Pina

Allan Bradley

Irmela Jeremias

DAVID BATES David.Bates@nottingham.ac.uk
Professor of Oncology

Kosuke Yusa

Tony Kouzarides

George S. Vassiliou



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., …Vassiliou, G. S. (2018). SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4. Nature Communications, 9(1), 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

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