High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-X-L in chronic myeloid leukemia



Lucas, CM ORCID: 0000-0001-6674-7535, Milani, M, Butterworth, M, Carmell, N, Scott, LJ, Clark, RE ORCID: 0000-0002-1261-3299, Cohen, GM and Varadarajan, S ORCID: 0000-0002-8827-6567
(2016) High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-X-L in chronic myeloid leukemia. LEUKEMIA, 30 (6). 1273 - 1281.

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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.

Item Type: Article
Uncontrolled Keywords: Chronic myeloid leukaemia, Prognosis, Targeted therapies, Translational research, Tumour biomarkers
Depositing User: Symplectic Admin
Date Deposited: 11 Apr 2016 14:14
Last Modified: 17 Oct 2020 14:11
DOI: 10.1038/leu.2016.42
Related URLs:
URI: http://livrepository.liverpool.ac.uk/id/eprint/3000182