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.
• Carmell, N.
• Scott, L.J.
• Clark, R.E.
• Cohen, G.M.
• Varadarajan, S.

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.

• Published: 1 June 2016
• Published (online): 18 March 2016
• Accepted: 12 February 2016

• Author