SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4
| العنوان: | SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4 |
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| المؤلفون: | Emmanouil Metzakopian, Demetrios Aspris, Paolo Gallipoli, Tony Kouzarides, Francisco Hermida-Prado, Rab K. Prinjha, Isaia Barbieri, Roya Babaei-Jadidi, Samuel Robson, Irmela Jeremias, John C. Marioni, Michael Seiler, João M. L. Dias, Cristina Pina, Kosuke Yusa, Malgorzata Gozdecka, Silvia Buonamici, Yu Hsuen Yang, Etienne De Braekeleer, Brian J. P. Huntly, Allan Bradley, Binje Vick, Andrew J. Bannister, Hannes Ponstingl, Monika Dudek, Hamish D. Toop, M. S. Vijayabaskar, David O. Bates, Wen-Hsin Liu, George S. Vassiliou, Jennifer Batson, Jonathan C. Morris, Dimitrios A. Garyfallos, Konstantinos Tzelepis, Roland Rad |
| المساهمون: | Toop, Hamish D [0000-0003-4637-4764], Ponstingl, Hannes [0000-0001-7573-1703], Dias, Joao ML [0000-0002-8451-3537], Gallipoli, Paolo [0000-0001-7254-2253], Vick, Binje [0000-0003-1956-2778], Prinjha, Rab K [0000-0002-2666-3326], Marioni, John C [0000-0001-9092-0852], Huntly, Brian [0000-0003-0312-161X], Batson, Jennifer [0000-0001-7005-4336], Morris, Jonathan C [0000-0002-5109-9069], Jeremias, Irmela [0000-0003-1773-7677], Vassiliou, George S [0000-0003-4337-8022], Apollo - University of Cambridge Repository |
| المصدر: | Nature Communications Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) Nat. Commun. 9:5378 (2018) Tzelepis, K, De Braekeleer, E, Aspris, D, Barbieri, I, Vijayabaskar, M S, Liu, W, 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, Buonamici, S, Vick, B, Bannister, A J, Rad, R, Prinjha, R K, Marioni, J C, Huntly, B, Batson, J, Morris, J C, Pina, C, Bradley, A, Jeremias, I, Bates, D O, Yusa, K, Kouzarides, T & Vassiliou, G S 2018, ' SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4 ', Nature Communications, vol. 9, no. 1, 5378 . https://doi.org/10.1038/s41467-018-07620-0Test |
| بيانات النشر: | Nature Publishing Group UK, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Gene isoform, BRD4, Cellular differentiation, Science, RNA Splicing, General Physics and Astronomy, Cell Cycle Proteins, HL-60 Cells, Biology, SRPK1, Protein Serine-Threonine Kinases, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Paediatric cancer, 03 medical and health sciences, Targeted therapies, Cancer epigenetics, hemic and lymphatic diseases, Humans, Protein Isoforms, MYB, Epigenetics, lcsh:Science, neoplasms, Multidisciplinary, Biomedical Sciences, Myeloid leukemia, Nuclear Proteins, Cell Differentiation, General Chemistry, Cell Cycle Checkpoints, Chromatin, 3. Good health, Hematopoiesis, Leukemia, Myeloid, Acute, 030104 developmental biology, Cancer research, lcsh:Q, K562 Cells, Transcription Factors |
| الوصف: | 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. SRPK1, a kinase involved in splicing regulation, is a potential therapeutic target for AML patients. Here, the authors show that SRPK1 inhibition changes isoform levels of key epigenetic regulators, including BRD4, and it has anti-tumor effects specifically against MLL-rearranged AML cells. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0b977c8316956d534c8b30c77125f51fTest http://europepmc.org/articles/PMC6300607Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0b977c8316956d534c8b30c77125f51f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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