title: Leukemic target susceptibility to natural killer cytotoxicity: relationship with BCR-ABL expression.
abstract: 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.
authors.affiliation: INSERM 487, Laboratoire de thérapie cellulaire, Institut Gustave Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baron
authors.forename: Ali G
authors.initials: AG
authors.lastname: Turhan
authors.forename: Julien
authors.initials: J
authors.lastname: Giron-Michel
authors.forename: Bruno
authors.initials: B
authors.lastname: Azzarone
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bentires-Alj
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.forename: Jean Henri
authors.initials: JH
authors.lastname: Bourhis
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.forename: Anne
authors.initials: A
authors.lastname: Caignard
mesh_terms: 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
chemical_list: D018952:Antigens, CD34; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D016044:Fusion Proteins, bcr-abl