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 - 2018/12/19
Y1 - 2018/12/19
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 - http://www.scopus.com/inward/record.url?scp=85058862327&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-07620-0
DO - 10.1038/s41467-018-07620-0
M3 - Article
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5378
ER -