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

Lucas, C.M., Milani, M., Butterworth, M. et al. (5 more authors) (2016) High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia. Leukemia, 30 (6). pp. 1273-1281. ISSN 0887-6924

Abstract

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Authors/Creators:
  • Lucas, C.M.
  • Milani, M.
  • Butterworth, M.
  • Carmell, N.
  • Scott, L.J.
  • Clark, R.E.
  • Cohen, G.M.
  • Varadarajan, S.
Copyright, Publisher and Additional Information: 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-X L . 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-X L via RNA interference or A-1331852, a novel, potent and BCL-X L -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-X L is the major antiapoptotic survival protein and may be a novel therapeutic target in CML.
Dates:
  • Published: 1 June 2016
  • Accepted: 12 February 2016
  • Published (online): 18 March 2016
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology (Sheffield)
Depositing User: Symplectic Sheffield
Date Deposited: 21 Jul 2016 09:44
Last Modified: 21 Jul 2016 09:44
Published Version: http://dx.doi.org/10.1038/leu.2016.42
Status: Published
Publisher: Nature Publishing Group
Refereed: Yes
Identification Number: https://doi.org/10.1038/leu.2016.42
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