a-1331852 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

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.

Topics: Adolescent; Adult; Aged; Apoptosis; Autoantigens; bcl-X Protein; Benzothiazoles; Biomarkers, Tumor; Cell Line, Tumor; Female; Humans; Intracellular Signaling Peptides and Proteins; Isoquinolines; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Membrane Proteins; Middle Aged; Prognosis; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Young Adult