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Nat Commun. 2018 Dec 19;9(1):5378. doi: 10.1038/s41467-018-07620-0.

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

Author information

1
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK. kt404@cam.ac.uk.
2
Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge, CB2 1QN, UK. kt404@cam.ac.uk.
3
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
4
Karaiskakio Foundation, Nicosia, Cyprus.
5
Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, CB2 0QQ, Cambridge, UK.
6
Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 81377, Munich, Germany.
7
Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK.
8
UK Dementia Research Institute, University of Cambridge, Hills Rd, Cambridge, CB2 0AH, UK.
9
School of Chemistry, University of New South Wales, Sydney, Australia.
10
Exonate Ltd, Milton Science Park, Cambridge, UK.
11
School of Pharmacy and Biomedical Science, University of Portsmouth, White Swan Road, Portsmouth, PO1 2DT, UK.
12
Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
13
Cancer Molecular Diagnosis Laboratory, National Institute for Health Research, Biomedical Research Centre, University of Cambridge, Cambridge, UK.
14
Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK.
15
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, CB2 0QQ, UK.
16
H3 Biomedicine Inc., Cambridge, MA, USA.
17
Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge, CB2 1QN, UK.
18
Institute of Molecular Oncology and Functional Genomics, Department of Medicine II and TranslaTUM Cancer Center, Technical University of Munich, Germany.
19
German Cancer Research Center (DKFZ), Heidelberg, & German Cancer Consortium (DKTK), Heidelberg, Germany.
20
Epigenetics DPU, Immunoinflammation and Oncology TA Unit, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
21
Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK.
22
European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK.
23
Stem Cell Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
24
Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University München, 80337, Munich, Germany.
25
Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, NG2 7UH, UK.
26
Stem Cell Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK. ky1@sanger.ac.uk.
27
Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge, CB2 1QN, UK. t.kouzarides@gurdon.cam.ac.uk.
28
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK. gsv20@sanger.ac.uk.
29
Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK. gsv20@sanger.ac.uk.
30
Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK. gsv20@sanger.ac.uk.

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.

PMID:
30568163
PMCID:
PMC6300607
DOI:
10.1038/s41467-018-07620-0
[Indexed for MEDLINE]
Free PMC Article

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