BCR/ABL Promotes Dendritic Cell–Mediated Natural Killer Cell Activation Magali Terme, 1 Christophe Borg, 1 Franc ¸ois Guilhot, 5 Carole Masurier, 1,6 Caroline Flament, 1 Erwin F. Wagner, 7 Sophie Caillat-Zucman, 8 Alain Bernheim, 2 Ali G. Turhan, 3 Anne Caignard, 4 and Laurence Zitvogel 1 1 ERM0208 Institut National de la Sante et de la Recherche Medicale, Department of Clinical Biology, Institut Gustave Roussy; 2 Cytogenetic and Oncologic Genetic Laboratory, Institut Gustave Roussy; 3 Translational Research-Cell Therapy Laboratory and Institut National de la Sante et de la Recherche Medicale U362, Institut Gustave Roussy; 4 U487 Institut National de la Sante et de la Recherche Medicale, Villejuif, France; 5 Oncology Hematology and Cell Therapy, CHU La Mile´trie, Poitiers, France; 6 Immunology Laboratory, Centre National de la Recherche Scientifique UMR8115, Genethon, Evry, France; 7 Institute of Molecular Pathology, Vienna, Austria; and 8 Laboratoire d’Immunologie Clinique, Ho ˆpital Necker-Enfants malades, Paris, France Abstract BCR/ABL fusion gene, encoding a paradigmatic tyrosine kinase involved in chronic myelogenous leukemia (CML), can modu- late 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 BCR/ABL is necessary to promote dendritic cell–mediated NK cell activation. The dendritic cell/ NK cell cross-talk in BCR/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, BCR/ABL translocation enhances the expression levels of the NKG2D ligands on dendritic cells, which is counteracted by imatinib mesylate. Altogether, the clonal BCR/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. (Cancer Res 2005; 65(14): 6409-17) Introduction Chronic myelogenous leukemia (CML) is a clonal malignancy of the hematopoietic stem cell harboring a 9;22 translocation which fuses the ABL proto-oncogene to the BCR gene leading to constitutive tyrosine kinase activity necessary and sufficient for massive overproduction of granulocytic cells (1). Natural killer (NK) cells may be involved in the control of the malignant CML clone (2). The efficacy of graft-versus-leukemia effect following allogeneic stem cell bone marrow transplantation in CML prompted the search for immune effectors. The role of NK cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation has been recently unraveled (3, 4). In addition, Cervantes et al. (5) previously showed that interleukin (IL)-2–activated NK cells from patients with CML suppress autologous primitive CML progenitors in long-term culture. Moreover, BCR/ABL confers to target cell susceptibility to NK cell lysis (6). However, NK cells from CML patients (CML-NK) gradually decrease in number during disease progression from chronic phase to blast crisis (7). The BCR/ABL transgene in CD34 + DR + cells causes abnormal NK cell differentiation (8, 9). CML-NK cells proliferate less in response to IL-2 stimulation (7). Interestingly, significant numbers of NK cells from advanced-phase CML patients are BCR/ABL + whereas T cells remain negative regardless of the disease stage. Chiorean et al. (10) have recently shown that BCR/ ABL directly alters the function of NK cells (i.e., induces partial IL-2 independent growth and increases killer immunoglobulin-like receptor expression in primary CD56 bright NK cell subsets). We described in 1999 that dendritic cells have unique capacities to trigger NK cell effector functions in vitro (11). Dendritic cell– mediated NK cell activation can lead to the control of ( a ) viral replication (12) and (b) the growth of NK cell–sensitive tumors (11, 13). Human studies have clearly shown that mostly mature dendritic cells [i.e., cells activated by lipopolysaccharide (LPS) or type I IFN or mycobacteria] are endowed with NK cell stimulatory capacities in vitro (14–18). In CML patients, between 73% and 100% of monocyte-derived dendritic cells (CML dendritic cells) are positive for the chimeric BCR/ABL gene (19, 20). Many reports showed that dendritic cells derived from both normal volunteers (normal dendritic cells) and CML patients differentiated and matured in culture (19, 21–24) but there are conflicting data regarding the ability of CML dendritic cells compared with normal dendritic cells to stimulate T cells (19, 20, 25–31). However, the effects of BCR/ABL translocation on the capacity of dendritic cells to activate NK cells have never been studied. Here we show that the BCR/ABL translocation specifically confers to dendritic cells a selective NK cell stimulatory function by up- regulating the expression of NKG2D ligands in both mouse and human models. Materials and Methods Patients Blood samples were collected from CML patients and normal volunteers concurrently after informed consent. Clinical status and current treatment are described in Table 1. Most patients presented with CML in chronic Note: The first authors M. Terme and C. Borg, and the last authors A. Caignard and L. Zitvogel have equally contributed to the work. Requests for reprints: Laurence Zitvogel, Immunology Unit, ERM0208 Institut National de la Sante et de la Recherche Medicale, Department of Clinical Biology, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. Phone: 33-1-42-11-50-41; Fax: 33-1-42-11-60-94; E-mail: zitvogel@igr.fr. I2005 American Association for Cancer Research. www.aacrjournals.org 6409 Cancer Res 2005; 65: (14). July 15, 2005 Research Article Research. on February 21, 2016. © 2005 American Association for Cancer cancerres.aacrjournals.org Downloaded from