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dc.contributor.authorLucas, Claire*
dc.contributor.authorMilani, Mateus*
dc.contributor.authorButterworth, Michael*
dc.contributor.authorCarmell, Natasha*
dc.contributor.authorScott, Laura*
dc.contributor.authorClark, Richard E.*
dc.contributor.authorCohen, Gerald*
dc.contributor.authorVaradarajan, Shankar*
dc.date.accessioned2019-04-23T15:22:24Z
dc.date.available2019-04-23T15:22:24Z
dc.date.issued2016-02-29
dc.identifier.citationLucas, 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.issn0887-6924
dc.identifier.doi10.1038/leu.2016.42.
dc.identifier.urihttp://hdl.handle.net/10034/622168
dc.description.abstractCancerous 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.isoenen
dc.publisherNatureen_US
dc.relation.urlhttps://www.nature.com/articles/leu201642en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectcmlen_US
dc.subjectapoptosisen_US
dc.subjectbclxlen_US
dc.subjectbiomarkersen_US
dc.titleHigh CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia.en_US
dc.typeArticleen_US
dc.identifier.eissn1476-5551
dc.contributor.departmentUniversity of Liverpool
dc.identifier.journalLeukemiaen_US
dc.date.accepted2016-02-12
or.grant.openaccessYesen_US
rioxxterms.fundern/aen_US
rioxxterms.identifier.projectn/aen_US
rioxxterms.versionVoRen_US
rioxxterms.versionofrecordhttp://doi.org/10.1038/leu.2016.42.
rioxxterms.licenseref.startdate2016-02-29


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