• Authors: Lucas, C. M., Milani, M., Butterworth, M., Carmell, N., Scott, L. J., Clark, R. E., Cohen, G. M., Varadarajan, S.
  • Year: 2016
  • Journal: Leukemia 30 1273-81
  • Applications: in vitro / siRNA / INTERFERin
  • Cell types:
    1. Name: K-562
      Description: Human chronic myelogenous leukaemia cells
      Known as: K562
    2. Name: KCL-22
      Description: human chronic myelogenous leukemia cell line.


Cells were reverse-transfected with 10 nM of siRNA using INTERFERin according to the manufacturer's protocol, and analysed 48h post-transfection.


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.