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

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; 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; George S. Vassiliou

doi:10.1038/s41467-018-07620-0

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

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
, 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, George S. Vassiliou

^*Corresponding author for this work

Wellcome Sanger Institute
Wellcome Trust/ Cancer Research UK Gurdon Institute
Karaiskakio Foundation
University of Cambridge
Helmholtz Zentrum München - German Research Center for Environmental Health
University of New South Wales
Exonate Ltd.
University of Portsmouth
Cambridge University Hospitals NHS Foundation Trust
Eisai Co., Ltd.
Technical University of Munich
German Cancer Research Center
GlaxoSmithKline
European Molecular Biology Laboratory
Ludwig Maximilian University of Munich
University of Nottingham

Research output: Contribution to journal › Article › Academic › peer-review

14 Downloads (Pure)

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.

Original language	English
Article number	5378
Journal	Nat. Commun.
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07620-0
Publication status	Published - 1 Dec 2018
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1038/s41467-018-07620-0

Srpk1-maintains-acute-myeloid-leukemia-through-effects-on-isoform-usage-of-epigenetic-regulators-including-brd4.pdfFinal published version, 2.02 MBLicence: CC BY

Cite this

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., ... Vassiliou, G. S. (2018). SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4. Nat. Commun., 9(1), Article 5378. https://doi.org/10.1038/s41467-018-07620-0

@article{ab8bcdd3001e4b80926b9b7377e3805a,

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.",

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

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-07620-0",

language = "English",

volume = "9",

journal = "Nat. Commun.",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Tzelepis, K, de Braekeleer, E, Aspris, D, Barbieri, I, Vijayabaskar, MS, Liu, W-H, Gozdecka, M, Metzakopian, E, Toop, HD, Dudek, M, Robson, SC, Hermida-Prado, F, Yang, YH, Babaei-Jadidi, R, Garyfallos, DA, Ponstingl, H, Dias, JML, Gallipoli, P, Seiler, M, Buonamici, S, Vick, B, Bannister, AJ, Rad, R, Prinjha, RK, Marioni, JC, Huntly, B, Batson, J, Morris, JC, Pina, C, Bradley, A, Jeremias, I, Bates, DO, Yusa, K, Kouzarides, T & Vassiliou, GS 2018, 'SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4', Nat. Commun., vol. 9, no. 1, 5378. https://doi.org/10.1038/s41467-018-07620-0

TY - JOUR

T1 - SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4

AU - Tzelepis, Konstantinos

AU - de Braekeleer, Etienne

AU - Aspris, Demetrios

AU - Barbieri, Isaia

AU - Vijayabaskar, M. S.

AU - Liu, Wen-Hsin

AU - Gozdecka, Malgorzata

AU - Metzakopian, Emmanouil

AU - Toop, Hamish D.

AU - Dudek, Monika

AU - Robson, Samuel C.

AU - Hermida-Prado, Francisco

AU - Yang, Yu Hsuen

AU - Babaei-Jadidi, Roya

AU - Garyfallos, Dimitrios A.

AU - Ponstingl, Hannes

AU - Dias, Joao M. L.

AU - Gallipoli, Paolo

AU - Seiler, Michael

AU - Buonamici, Silvia

AU - Vick, Binje

AU - Bannister, Andrew J.

AU - Rad, Roland

AU - Prinjha, Rab K.

AU - Marioni, John C.

AU - Huntly, Brian

AU - Batson, Jennifer

AU - Morris, Jonathan C.

AU - Pina, Cristina

AU - Bradley, Allan

AU - Jeremias, Irmela

AU - Bates, David O.

AU - Yusa, Kosuke

AU - Kouzarides, Tony

AU - Vassiliou, George S.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85058862327

UR - https://www.ncbi.nlm.nih.gov/pubmed/30568163

U2 - 10.1038/s41467-018-07620-0

DO - 10.1038/s41467-018-07620-0

M3 - Article

C2 - 30568163

SN - 2041-1723

VL - 9

JO - Nat. Commun.

JF - Nat. Commun.

IS - 1

M1 - 5378

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this