High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia.
dc.contributor.author | Lucas, Claire | * |
dc.contributor.author | Milani, Mateus | * |
dc.contributor.author | Butterworth, Michael | * |
dc.contributor.author | Carmell, Natasha | * |
dc.contributor.author | Scott, Laura | * |
dc.contributor.author | Clark, Richard E. | * |
dc.contributor.author | Cohen, Gerald | * |
dc.contributor.author | Varadarajan, Shankar | * |
dc.date.accessioned | 2019-04-23T15:22:24Z | |
dc.date.available | 2019-04-23T15:22:24Z | |
dc.date.issued | 2016-02-29 | |
dc.identifier.citation | Lucas, C. M., Milani, M., Butterworth, M., Carmell, N., Scott, L. J., Clark, R. E., . . . Varadarajan, S. (2016). High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia. Leukemia, 30(6), 1273-1281. | |
dc.identifier.issn | 0887-6924 | |
dc.identifier.doi | 10.1038/leu.2016.42. | |
dc.identifier.uri | http://hdl.handle.net/10034/622168 | |
dc.description.abstract | Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a predictive biomarker of disease progression in many malignancies, including imatinib-treated chronic myeloid leukemia (CML). Although high CIP2A levels correlate with disease progression in CML, the underlying molecular mechanisms remain elusive. In a screen of diagnostic chronic phase samples from patients with high and low CIP2A protein levels, high CIP2A levels correlate with an antiapoptotic phenotype, characterized by downregulation of proapoptotic BCL-2 family members, including BIM, PUMA and HRK, and upregulation of the antiapoptotic protein BCL-XL. These results suggest that the poor prognosis of patients with high CIP2A levels is due to an antiapoptotic phenotype. Disrupting this antiapoptotic phenotype by inhibition of BCL-XL via RNA interference or A-1331852, a novel, potent and BCL-XL-selective inhibitor, resulted in extensive apoptosis either alone or in combination with imatinib, dasatinib or nilotinib, both in cell lines and in primary CD34(+) cells from patients with high levels of CIP2A. These results demonstrate that BCL-XL is the major antiapoptotic survival protein and may be a novel therapeutic target in CML. | |
dc.language.iso | en | en |
dc.publisher | Nature | en_US |
dc.relation.url | https://www.nature.com/articles/leu201642 | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | cml | en_US |
dc.subject | apoptosis | en_US |
dc.subject | bclxl | en_US |
dc.subject | biomarkers | en_US |
dc.title | High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia. | en_US |
dc.type | Article | en_US |
dc.identifier.eissn | 1476-5551 | |
dc.contributor.department | University of Liverpool | |
dc.identifier.journal | Leukemia | en_US |
dc.date.accepted | 2016-02-12 | |
or.grant.openaccess | Yes | en_US |
rioxxterms.funder | n/a | en_US |
rioxxterms.identifier.project | n/a | en_US |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | http://doi.org/10.1038/leu.2016.42. | |
rioxxterms.licenseref.startdate | 2016-02-29 |