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.
Highlights
Chronic myeloid leukemia (CML) is a malignant disease of a primitive hematopoietic cell, characterized by a reciprocal translocation between chromosomes 9 and 22 and creates the fusion gene BCR-ABL1, which is a deregulated tyrosine kinase that drives the leukemia.[1]
tyrosine kinase inhibitor (TKI) prime CML cell lines to undergo apoptosis Since high levels of cancerous inhibitor of phosphatase 2A (PP2A) (CIP2A) contributed to imatinib resistance in CML, we wished to understand the role of BCL-2 family members in this resistance mechanism
All BH3-only activators exhibited extensive mitochondrial depolarization, BH3-only sensitizers demonstrated greater selectivity as demonstrated by a concentration-dependent loss in φm following BMF, BAD and HRK, but not NOXA (Figure 1a and Supplementary Figure S1). These results suggested that the survival of these cells depended more on BCL-2, BCL-XL and BCL-w, rather than on MCL-1 and BFL-1, as NOXA was the only sensitizer among the list to target both MCL-1 and BFL-1 (Figure 1a and Supplementary Figure S1).[9,10,11]
Summary
Chronic myeloid leukemia (CML) is a malignant disease of a primitive hematopoietic cell, characterized by a reciprocal translocation between chromosomes 9 and 22 and creates the fusion gene BCR-ABL1, which is a deregulated tyrosine kinase that drives the leukemia.[1] CML treatment has been significantly improved by the tyrosine kinase inhibitor (TKI) imatinib, but some patients will eventually fail imatinib treatment and without a change in therapy, a significant proportion will progress towards blast crisis (BC), which is usually rapidly fatal.[2,3] The kinase activity of BCR-ABL is opposed by cellular phosphatases, such as protein phosphatase 2A (PP2A), which is impaired in several malignancies. CIP2A inhibits PP2A activity and functions by preventing PP2A-driven dephosphorylation and stabilization of c-Myc.[6,7,8] CIP2A is a strong prospective predictor of subsequent development of BC in imatinib-treated CML patients,[5] the underlying mechanisms remain unclear
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