BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors.
| dc.contributor.author | Korfi, Koorosh | |
| dc.contributor.author | Smith, Matthew | |
| dc.contributor.author | Swan, Jacqueline | |
| dc.contributor.author | Somervaille, Tim C P | |
| dc.contributor.author | Dhomen, Nathalie | |
| dc.contributor.author | Marais, Richard | |
| dc.date.accessioned | 2016-04-22T15:07:07Z | en |
| dc.date.available | 2016-04-22T15:07:07Z | en |
| dc.date.issued | 2016 | en |
| dc.identifier.citation | BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors. 2016, 7:e2177 Cell Death Dis | en |
| dc.identifier.issn | 2041-4889 | en |
| dc.identifier.pmid | 27054332 | en |
| dc.identifier.doi | 10.1038/cddis.2016.70 | en |
| dc.identifier.uri | http://hdl.handle.net/10541/606632 | en |
| dc.description.abstract | B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1(+) patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential. | |
| dc.language.iso | en | en |
| dc.rights | Archived with thanks to Cell death & disease | en |
| dc.title | BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors. | en |
| dc.type | Article | en |
| dc.contributor.department | Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester | en |
| dc.identifier.journal | Cell Death & Disease | en |
| html.description.abstract | B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1(+) patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential. |