Loading...
High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia.
Lucas, Claire Milani, Mateus Butterworth, Michael Carmell, Natasha Scott, Laura Clark, Richard E. Cohen, Gerald Varadarajan, Shankar
Lucas, Claire
Milani, Mateus
Butterworth, Michael
Carmell, Natasha
Scott, Laura
Clark, Richard E.
Cohen, Gerald
Varadarajan, Shankar
Citations
Altmetric:
Advisors
Editors
Other Contributors
Affiliation
EPub Date
Publication Date
2016-02-29
Submitted Date
Collections
Files
Loading...
Manuscript
Adobe PDF, 1.99 MB
Other Titles
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.
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.
Publisher
Nature
Journal
Leukemia
Research Unit
PubMed ID
PubMed Central ID
Type
Article
Language
en
Description
Series/Report no.
ISSN
0887-6924
EISSN
1476-5551