The effects of STI571 on antigen presentation of dendritic cells generated from patients with chronic myelogenous leukemia

Abstract

Chronic myelogenous leukemia is caused by the acquisition of the reciprocal (9;22)(q34;q11) chromosomal translocation in hematopoietic stem cells. The fusion protein showed higher and aberrant tyrosine kinase activity. The inhibition of the tyrosine kinase activity of the protein represents a specific therapeutic strategy for bcr/abl-expressing leukemias. STI571 is a compound of the 2-phenylaminopyrimidine class that selectively inhibits the tyrosine kinase activity of the Abl protein tyrosine kinase. In this study, we evaluated the effects of STI571 on antigen presentation of dendritic cells generated from the patients with CML. The data showed that by the addition of STI571 the dendritic cells derived from CML clone showed an increased expression of CD1a, CD83, CD80 and CD86 by flow cytometry analysis and showed more intense abilities of allogeneic antigen presentation by mixed leukocyte culture, compared with the control cells without STI571. Our results suggested that STI571 not only has a direct cytotoxic effect on bcr-abl gene rearranged cells but also an indirect effect associated with increased anti-leukemic immunological function due to an intensified antigen presentation.

Effects of Imatinib on Monocyte-Derived Dendritic Cells Are Mediated by Inhibition of Nuclear Factor-κB and Akt Signaling Pathways

“…In contrast to our findings, Sato et al showed that antigen presentation of dendritic cells from CML patients is restored by addition of imatinib (63). However, Bcr-Abl-positive dendritic cells are functionally defective and differ from normal dendritic cells.…”

Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

“…These in vitro observations have been confirmed by data from a mouse model [18]. In contrast, it has also been shown that imatinib does not affect CML-DC phenotype, migration profile or T-cell stimulatory capacity [19] and CML-DC display even improves antigen presentation abilities in the presence of imatinib [20]. In mice, DC treated with imatinib have exhibited enhanced APC function [21].…”

Imatinib mesylate does not impair the immunogenicity of human myeloid blood dendritic cells

“…The authors' speculation that the effect was related to an antileukemic role of reconstituting natural killer (NK) cells is plausible, as T-cell immunological reconstitution is profoundly impaired in patients undergoing intensive chemotherapy. 2 Our own investigations of the antileukemia activity of human leukocyte antigen (HLA)-matched and autologous NK cells in myelogenous leukemia after allogeneic hematopoietic stem cell transplantation (SCT) also support a role for autologous NK cells in myeloid malignancies. 3,4 The missing self-hypothesis 5 does not explain the antileukemic activity of autologous or allogeneic HLA-matched NK cells, as myelogenous leukemia cells always retain HLA class I antigen expression.…”

“…Thus, it has been shown that CML-derived DCs display an improved ability of antigen presentation in the presence of imatinib. 2 Further data revealed that imatinib does neither inhibit the immunophenotypic profile and migration of CML-derived DCs nor their ability to stimulate T-cell proliferation (below 2.5 mM imatinib). 3 More recently, it has been reported that exposure to imatinib only minimally affects the differentiation of bcr-abl þ and normal monocytes into DCs and does not impair the DC-mediated polarization of naive CD4 þ T cells.…”