Survivin isoform expression in arsenic trioxide-treated acute promyelocytic leukemia cell line and patients: The odd expression pattern of survivin-2α.

Abstract

Survivin, an inhibitor of apoptosis protein, is overexpressed in most cancers and is associated with chemotherapy resistance, increased tumor recurrence and shorter patient survival. Several survivin splice variants have been described, and none of their expressions have been defined in acute promyelocytic leukemia (APL). Expression of the survivin gene isoforms (survivin, -2α, -2B, -ΔΕx3 and -3B) were analyzed in 50 peripheral blood and 19 bone marrow samples that were collected at different phases of the disease (diagnostic, remission and relapse) in APL patients treated with arsenic trioxide (ATO) as a front-line therapy. In addition, the human APL-derived cell line (NB4) was analyzed for the expression of survivin isoforms and capsase-3 in response to the ATO. Survivin and its variants were overexpressed significantly in patient's bone marrow samples compared to peripheral blood or normal samples. Their expression was decreased after ATO treatment in both NB4 cells (except survivin-2α) and APL patients along with PML-RARα copy number reduction. Downregulation of survivin isoforms was associated with an increase in both caspase-3 gene expression and its enzymatic activity levels. In a patient who did not respond to ATO treatment, expression of survivin isoforms (except survivin-2α) were highly increased during the induction therapy. Survivin isoforms are upregulated in APL patients, and their expression is diminished during the ATO treatment. In addition, overexpression of survivin and its variants (except survivin-2α) are associated with unfavorable results, suggesting that they may play an important role in mechanisms underlying the resistance of APL cells to ATO.