The decreased susceptibility of Bcr/Abl targets to NK cell-mediated lysis in response to imatinib mesylate involves modulation of NKG2D ligands, GM1 expression, and synapse formation.
Chronic myeloid leukemia is a clonal multilineage myeloproliferative disease of stem cell origin characterized by the presence of the Bcr/Abl oncoprotein, a constitutively active tyrosine kinase. In previous studies, we have provided evidence that Bcr/Abl overexpression in leukemic cells increased their susceptibility to NK-mediated lysis by different mechanisms. In the present study, using UT-7/9 cells, a high level Bcr/Abl transfectant of UT-7 cells, we show that the treatment of Bcr/Abl target by imatinib mesylate (IM), a specific Abl tyrosine kinase inhibitor, hampers the formation of the NK/target immunological synapse. The main effect of IM involves an induction of surface GM1 ganglioside on Bcr/Abl transfectants that prevents the redistribution of MHC-related Ag molecules in lipid rafts upon interaction with NK cells. IM also affects cell surface glycosylation of targets, as assessed by binding of specific lectins resulting in the subsequent modulation of their binding to lectin type NK receptor, particularly NKG2D. In addition, we demonstrate that the tyrosine kinase activity repression results in a decrease of MHC-related Ags-A/B and UL-16-binding protein expression on Bcr/Abl transfectants UT-7/9. We show that NKG2D controls the NK-mediated lysis of UT-7/9 cells, and IM treatment inhibits this activating pathway. Taken together, our results show that the high expression of Bcr/Abl in leukemic cells controls the expression of NKG2D receptor ligands and membrane GM1 via a tyrosine kinase-dependent mechanism and that the modulation of these molecules by IM interferes with NK cell recognition and cytolysis of the transfectants.
Cebo
Christelle
C
Institut National de la Santé et de la Recherche Médicale, Unité 487, Institut Gustave Roussy, Villejuif, France.
Da Rocha
Sylvie
S
Wittnebel
Sebastian
S
Turhan
Ali G
AG
Abdelali
Jalil
J
Caillat-Zucman
Sophie
S
Bourhis
Jean Henri
JH
Chouaib
Salem
S
Caignard
Anne
A
D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005677:G(M1) Ganglioside / Q000378:metabolism*; D016313:Genes, abl; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D014162:Transfection
D000970:Antineoplastic Agents; D001549:Benzamides; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010879:Piperazines; D011743:Pyrimidines; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D005677:G(M1) Ganglioside; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl