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

Konstantinos Tzelepis (), Etienne 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, Roya Babaei-Jadidi, 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 O. Bates, Kosuke Yusa (), Tony Kouzarides () and George S. Vassiliou ()
Additional contact information
Konstantinos Tzelepis: Wellcome Trust Sanger Institute
Etienne Braekeleer: Wellcome Trust Sanger Institute
Demetrios Aspris: Wellcome Trust Sanger Institute
Isaia Barbieri: University of Cambridge, Addenbrookes Hospital
M. S. Vijayabaskar: Wellcome Trust Sanger Institute
Wen-Hsin Liu: German Research Center for Environmental Health (HMGU)
Malgorzata Gozdecka: Wellcome Trust Sanger Institute
Emmanouil Metzakopian: University of Cambridge
Hamish D. Toop: University of New South Wales
Monika Dudek: Wellcome Trust Sanger Institute
Samuel C. Robson: University of Portsmouth
Francisco Hermida-Prado: Wellcome Trust Sanger Institute
Yu Hsuen Yang: Wellcome Trust Sanger Institute
Roya Babaei-Jadidi: University of New South Wales
Dimitrios A. Garyfallos: Wellcome Trust Sanger Institute
Hannes Ponstingl: Wellcome Trust Sanger Institute
Joao M. L. Dias: University of Cambridge
Paolo Gallipoli: University of Cambridge
Michael Seiler: H3 Biomedicine Inc.
Silvia Buonamici: H3 Biomedicine Inc.
Binje Vick: German Research Center for Environmental Health (HMGU)
Andrew J. Bannister: Gurdon Institute and Department of Pathology
Roland Rad: Department of Medicine II and TranslaTUM Cancer Center
Rab K. Prinjha: GSK Medicines Research Centre
John C. Marioni: University of Cambridge
Brian Huntly: University of Cambridge
Jennifer Batson: Exonate Ltd, Milton Science Park
Jonathan C. Morris: University of New South Wales
Cristina Pina: University of Cambridge
Allan Bradley: Genome Campus
Irmela Jeremias: German Research Center for Environmental Health (HMGU)
David O. Bates: Exonate Ltd, Milton Science Park
Kosuke Yusa: Wellcome Trust Sanger Institute
Tony Kouzarides: Gurdon Institute and Department of Pathology
George S. Vassiliou: Wellcome Trust Sanger Institute

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07620-0

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