ORCID Profile
0000-0001-5702-9160
Current Organisation
University of Portsmouth
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Publisher: Springer Science and Business Media LLC
Date: 19-12-2018
DOI: 10.1038/S41467-018-07620-0
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.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 09-2012
Publisher: Public Library of Science (PLoS)
Date: 04-04-2013
Publisher: Springer Science and Business Media LLC
Date: 09-08-2013
DOI: 10.1038/LEU.2013.234
Abstract: Small molecule inhibition of the BET family of proteins, which bind acetylated lysines within histones, has been shown to have a marked therapeutic benefit in pre-clinical models of mixed lineage leukemia (MLL) fusion protein-driven leukemias. Here, we report that I-BET151, a highly specific BET family bromodomain inhibitor, leads to growth inhibition in a human erythroleukemic (HEL) cell line as well as in erythroid precursors isolated from polycythemia vera patients. One of the genes most highly downregulated by I-BET151 was LMO2, an important oncogenic regulator of hematopoietic stem cell development and erythropoiesis. We previously reported that LMO2 transcription is dependent upon Janus kinase 2 (JAK2) kinase activity in HEL cells. Here, we show that the transcriptional changes induced by a JAK2 inhibitor (TG101209) and I-BET151 in HEL cells are significantly over-lapping, suggesting a common pathway of action. We generated JAK2 inhibitor resistant HEL cells and showed that these retain sensitivity to I-BET151. These data highlight I-BET151 as a potential alternative treatment against myeloproliferative neoplasms driven by constitutively active JAK2 kinase.
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 07-10-2009
DOI: 10.1038/NATURE08516
Publisher: Springer Science and Business Media LLC
Date: 13-11-2013
DOI: 10.1038/LEU.2013.338
Publisher: Springer Science and Business Media LLC
Date: 10-2011
DOI: 10.1038/NATURE10509
Publisher: Springer Science and Business Media LLC
Date: 04-2010
DOI: 10.1038/NATURE08979
Publisher: Springer Science and Business Media LLC
Date: 28-10-2012
DOI: 10.1038/NG.2435
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Samuel Charles Robson.