Leukemic target susceptibility to natural killer cytotoxicity: relationship with BCR-ABL expression.
Chronic myeloid leukemia is a clonal myeloproliferative expansion of transformed primitive hematopoietic progenitor cells characterized by high-level expression of BCR-ABL chimeric gene, which induces growth factor independence. However, the influence of BCR-ABL expression on cell-mediated cytotoxicity is poorly understood. In the present study, we asked whether BCR-ABL expression interferes with leukemic target sensitivity to natural killer (NK) cell cytolysis. Our approach was based on the use of 2 BCR-ABL transfectants of the pluripotent hematopoietic cell line UT-7 expressing low (UT-7/E8, UT-7/G6) and high (UT-7/9) levels of BCR-ABL. As effector cells, we used CD56(bright), CD16-, CD2- NK cells differentiated in vitro from CD34 cord blood progenitors. We demonstrated that BCR-ABL transfectants UT-7/9 were lysed by NK cells with a higher efficiency than parental and low UT-7/E8.1 and UT-7/G6 transfectants. This enhanced susceptibility to lysis correlated with an increase in expression of intercellular adhesion molecule 1 (ICAM-1) by target cells. Treatment of UT-7/9 cells by STI571 (a specific inhibitor of the abl kinase) resulted in a decrease in NK susceptibility to lysis and ICAM-1 down-regulation in target cells. Furthermore, the constitutive activation of nuclear factor-kappaB (NF-kappaB) detected in BCR-ABL transfectant UT-7/9, was significantly attenuated when cells were treated by STI571. Interestingly, inhibition of NF-kappaB activation by BAY11-67082 (a specific NF-kappaB inhibitor) resulted in down-regulation of ICAM-1 expression and a subsequent decrease in NK-induced killing of UT-7/9 transfectants. Our results show that oncogenic transformation by BCR-ABL may increase susceptibility of leukemic progenitors to NK cell cytotoxicity by a mechanism involving overexpression of ICAM-1 as a consequence of NF-kappaB activation.
Baron
Frédéric
F
INSERM 487, Laboratoire de thérapie cellulaire, Institut Gustave Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, France.
Turhan
Ali G
AG
Giron-Michel
Julien
J
Azzarone
Bruno
B
Bentires-Alj
Mohamed
M
Bours
Vincent
V
Bourhis
Jean Henri
JH
Chouaib
Salem
S
Caignard
Anne
A
D018952:Antigens, CD34; D002454:Cell Differentiation; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D016044:Fusion Proteins, bcr-abl