title: The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia.
abstract: Soluble or membrane-anchored ligands of NKG2D and their receptor have a critical role in the elimination of tumor cells and disease progression. Plasma samples of 98 patients with B-cell chronic lymphocytic leukemia (CLL) were analyzed with specific ELISA systems for soluble major histocompatibility complex class I-related chains (sMICA and sMICB) and UL-16-binding proteins (ULBP1, 2, and 3). The flow cytometric analysis of MICA on CLL cells and natural killer group 2 member D (NKG2D) receptors on NK cells was performed after thawing of frozen peripheral blood lymphocytes of CLL patients (N=51). Levels of sMICA, sMICB, and sULBP2 were significantly increased (P<0.001) compared with 48 controls, whereas sULBP1 3 were not detectable in patients and controls. Levels of sMICA>990 pg/ml (P=0.014), sMICB>200 pg/ml (P=0.0001), and sULBP2>105 pg/ml (P<0.0001) were associated with poor treatment-free survival (TFS). Neither MICA nor NKG2D expression could be related to clinical parameters. In multivariate analysis Binet stage (P=0.002), sULBP2 (P=0.002) and ZAP-70 (P=0.002) were independent predictive factors for TFS. In patients with Binet stage A, sULBP2 levels>105 pg/ml were strongly associated (P=0.0025) with poor TFS. Our data show that soluble but not membrane-anchored NKG2D ligands or receptors are of prognostic significance in CLL. Moreover, sULBP2 seems to be useful to identify early-stage patients with risk of disease progression.
authors.affiliation: Department of Haematology, University Hospital Essen, Essen, Germany. holger.nueckel@uni-due.de
authors.forename: H
authors.initials: H
authors.lastname: Nückel
authors.forename: M
authors.initials: M
authors.lastname: Switala
authors.forename: L
authors.initials: L
authors.lastname: Sellmann
authors.forename: P A
authors.initials: PA
authors.lastname: Horn
authors.forename: J
authors.initials: J
authors.lastname: Dürig
authors.forename: U
authors.initials: U
authors.lastname: Dührsen
authors.forename: R
authors.initials: R
authors.lastname: Küppers
authors.forename: H
authors.initials: H
authors.lastname: Grosse-Wilde
authors.forename: V
authors.initials: V
authors.lastname: Rebmann
mesh_terms: D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I / Q000097:blood*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies
chemical_list: D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C099187:MHC class I-related chain A; C098080:MICB antigen; C423230:ULBP2 protein, human; C423229:ULBP3 protein, human