Calcium ionophore activation of chronic myelogenous leukemia progenitor cells into dendritic cells is mediated by calcineurin phosphatase.
We have previously demonstrated that Ph+ myeloid progenitor cells of patients with chronic myeloid leukemia (CML) can acquire characteristics of mature dendritic cells (DC) following calcium mobilization with calcium ionophore (A23187, CI). In this study we characterize the intracellular signaling pathway by which CI induces the acquisition of DC features in these leukemic cells. CI-induced activation of CML cells is attenuated by the calcineurin phosphatase inhibitor cyclosporin A (CsA) as well as the calmodulin (CaM) antagonist W-7. These cause ablation of both the CI-induced immunophenotypic expression of DC markers and immunostimulatory properties in mixed leukocyte responses (MLR). Minimal blocking effect was observed when Ca(2+)/CaM kinase II (281-301) inhibitor was added to the cultures. These findings suggest a Ca(2+)-dependent mechanism for the CI-induced activation of CML cells into antigen-presenting cells (APC), which is primarily mediated through the CaM/calcineurin pathway.
Engels
F H
FH
Department of Surgery, University of Pennsylvania Medical Center, 4 Silverstein Pavilion, 3400 Spruce Street, 19104-4283, Philadelphia, PA, USA. czerniec@mail.med.upenn.edu
Kreisel
D
D
Faries
M B
MB
Bedrosian
I
I
Koski
G K
GK
Cohen
P A
PA
Czerniecki
B J
BJ
D000001:Calcimycin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D003713:Dendritic Cells / Q000502:physiology*; D006801:Humans; D007476:Ionophores / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D023461:Myeloid Progenitor Cells / Q000187:drug effects*; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
D002147:Calmodulin; D007476:Ionophores; D013449:Sulfonamides; D000001:Calcimycin; C017967:W 7; D016572:Cyclosporine; C120817:calcineurin phosphatase; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium