Effects of STI571 on the Development of Dendritic Cells Derived from Bone Marrow Mononuclear Cells from Patients with Chronic Myeloid Leukemia.

Mature dendritc cells(DCs) are potent antigen-presenting cells that prime effective T-cell response aginst tumour antigens. However, in the tumour microenviroment the differentiation and maturation of DCs is always suppressed by many factors, such as VEGF, IL-10,TGF-βet al. Though DC derived from CML patients have been shown to process and present endogenous BCR-ABL to CD4+ T cells, the function of DC may be abnormal in CML, which have been shown differences in cytoskeletal organisation and impaired migration, and a reduced capacity to capture and present nonleukaemic antigen, and less effective than normal DC in eliciting an allogeneic mixed lymphocyte reaction. STI571(trade name Glivec or Gleevec) is a specific inhibitor of Abl tyrosine kinase and has been a first- line agent for the treatment of chronic myelogenous leukemia (CML). Previous studies have found that defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and can be partially normalized by STI571. We, therefore, explored whether treatment with STI571 may influence the CML -derived DC in vitro. Treatment bone marrow mononuclear cells(BMMNCs) of 11 patients with CML in chronic phase with STI571+rhGM-CSF+IL-4(STI571-DC) generated DCs with more mature phenotype properties expressing higher of CD80,CD86,HLA-DR,CD83 compared to the CML- BMMNCs treated with rhGM-CSF+IL-4(IL-4-DC). And in parallel with phenotypes, STI571-DC also showed more effective than IL-DC in eliciting an allogeneic mixed lymphocyte reaction by MTT assay. FISH confirmed the DCs of both groups were leukemic origin. To explore whether the positive effects of STI571 on CML-DC may attributed to negative factors of DC differentiation/maturation suppressed by STI571, media were tested for VEGF concentrations by using the sandwich enzyme-linked immunosorbent assay (ELISA). As a result, the concentration of VEGF was dramatically reduced in STI571-DC. These findings demonstrate that treatment with STI571 promotes maturation and enhances the antigen-presenting capabilities of CML- BMMNCs derived DCs, these studies also offer a more comprehensive understanding of the role of STI571 in the immunotherapy of CML.