Osteopontin b and c isoforms: Probably Unique Molecular Candidates Associated with Leukemic Stem Cells Chemoresistance in Acute Myeloid Leukemia

Abstract

Despite impressive advances in the therapeutic approches, the long-term survival rate of acute myeloid leukemia (AML) is considered to be significantly low as a result of resistance to the treatment and desease relapse. Among multitude oncogenic proteins invovlved in aquisition of chemo-resistance phenotype, osteopontin (OPN) recently attracted tremendous attentions. In spite of the well-defined association between OPN expression and cure rate in solid tumors, there is a scarcity of analysis on the role of this protein in AML. Based on the critical role of OPN in cell survival, it seems reasonable to hypothesize that the high expression of OPN isoforms may participate in disrupting the regulation of apoptosis in AML cells and it s relapse. To investigate the association between induction of apoptosis and OPN isoform expression, two distinct AML cell lines (KG-1 as a leukemic stem cell model and U937) were treated with chemotherapy drugs and the cell viability and apoptosis were evaluated by MTT and annexin/PI assay. After determination suitable drugs doses, the mRNA expression level of OPN and OPN-related genes were investigated. Our results demonstrated for the first time that the acquired up-regulation of OPN-b and c isoforms might prevent conventional chemotherapy regimen-induced apoptosis in AML cells. Moreover, the resulting data revealed that up-pregulation of OPN-b and c in AML cells was concurrently associated with the up-regulation of AKT, VEGF, CXCR4, STAT3 and IL-6 expression. To sum up, this study suggest that OPN-b and c isoforms could be considered as a unique beneficial molecular biomarker which is associated with chemoresistance. Hence, this isoforms are considerable as a potential moleculare candidate for detection of minimal residual disease (MRD) and determination of remission in AML patients. Furthure evaluation with quantative Real tim PCR on patient sample to comfim this finding seems to be be nessesary.