BCR/ABL promotes dendritic cell-mediated natural killer cell activation.
BCR/ABL fusion gene, encoding a paradigmatic tyrosine kinase involved in chronic myelogenous leukemia (CML), can modulate the expression of genes involved in natural killer (NK) cell target recognition. Recent reports outline the role of allogeneic antileukemic NK effectors in the graft-versus-leukemia effect but the regulation of NK cell activation in the setting of graft-versus-leukemia effect remains unknown. Here we show that dendritic cells derived from monocytes of CML patients are selectively endowed with NK cell stimulatory capacity in vitro. We further show, using a gene transfer approach in mouse bone marrow progenitors, that ABL/ABL is necessary to promote dendritic cell-mediated NK cell activation. The dendritic cell/NK cell cross-talk in ABL/ABL-induced CML seems unique because JunB or IFN consensus sequence binding protein loss of functions, associated with other myeloproliferative disorders, do not promote dendritic cell-mediated NK cell activation. NK cell activation by leukemic dendritic cells involves NKG2D activating receptors and is blocked by imatinib mesylate. Indeed, ABL/ABL translocation enhances the expression levels of the NKG2D ligands on dendritic cells, which is counteracted by imatinib mesylate. Altogether, the clonal ABL/ABL dendritic cells display the unique and selective ability to activate NK cells and may participate in the NK cell control of CML. This study also highlights the deleterious role of imatinib mesylate at the dendritic cell level for NK cell activation.
Terme
Magali
M
ERM0208 Institut National de la Sante et de la Recherche Medicale, Department of Clinical Biology, Institut Gustave Roussy, Villejuf Cedex, France.
Borg
Christophe
C
Guilhot
François
F
Masurier
Carole
C
Flament
Caroline
C
Wagner
Erwin F
EF
Caillat-Zucman
Sophie
S
Bernheim
Alain
A
Turhan
Ali G
AG
Caignard
Anne
A
Zitvogel
Laurence
L
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000276:immunology*; D018014:Gene Transfer Techniques; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000276:immunology; D055607:Receptors, Natural Killer Cell; D014178:Translocation, Genetic
C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D016044:Fusion Proteins, bcr-abl