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

摘要

Despite impressive advances in therapeutic approaches, long-term survival with acute myeloid leukemia (AML) is low as a result of treatment resistance and frequent relapse. Among multitude oncogenic proteins involved in the acquisition of a chemo-resistant phenotype, osteopontin (OPN) recently has attracted marked attention. In spite of the well-defined association between OPN expression and cure rate with solid tumors, there is a scarcity of information on any role of this protein in AML cases. Based on the critical role of OPN in cell survival, it seems reasonable to hypothesize that isoform expression levels may impact on the regulation of apoptosis in AML cells in response to conventional chemotherapeutic drugs and its relation to relapse. To investigate associations 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 cell viability and apoptosis were evaluated by MTT and Annexin/PI assay. After determination of appropriate drug doses, mRNA expression levels of OPN isoforms and OPN-related genes were investigated. Our results demonstrated for the first time that acquired up-regulation of OPN-b and c isoforms might prevent conventional chemotherapy regimen-induced apoptosis in AML cells. Moreover, upregulation of OPN-b and c in AML cells appears concurrent with upregulation of AKT/VEGF/CXCR4/STAT3/ IL-6 gene expression. To sum up, this study suggests that OPN-b and c isoforms could be considered as unique beneficial molecular biomarkers associated with leukemic stem cell chemoresistance. Hence, they have potential as molecular candidates for detection of minimal residual disease (MRD) and determination of remission in AML patients. Further evaluation with quantitative real time PCR on patient samples for confirmation appears warranted.