title: Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia.
abstract: Prognostic predictions in B-cell chronic lymphocytic leukemia (B-CLL) at early clinical stage are based on biological disease parameters, such as ZAP-70 and CD38 protein levels, genomic aberrations as well as immunoglobulin variable heavy chain gene (IgV(H)) mutation status. In the current study, ZAP-70 and CD38 expressions were examined by flow cytometry in 252 patients with B-CLL. Cytoplasmic ZAP-70 expression in more than 20% (ZAP-70(+)) and surface CD38 expression on more than 30% (CD38(+)) of B-CLL cells were associated with an unfavorable clinical course. The levels of ZAP-70 and CD38 did not change over time in the majority of patients where sequential samples were available for analysis. Combined analysis of ZAP-70 and CD38 yielded discordant results in 73 patients (29.0%), whereas 120 patients (47.6%) were concordantly negative and 59 patients (23.4%) were concordantly positive for ZAP-70 and CD38 expression. Median treatment-free survival times in patients whose leukemic cells were ZAP-70(+)CD38(+) was 30 months as compared to 130 months in patients with a ZAP-70(-)CD38(-) status. In patients with discordant ZAP-70/CD38 results, the median treatment-free survival time was 43 months. Thus, ZAP-70 and CD38 expression analyses provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. Over-representation of high-risk genomic aberrations such as 17p deletion or 11q deletion and distribution of the IgV(H) mutation status in B-CLL discordant for ZAP-70/CD38 pointed toward a distinct biologic background of the observed disease subgroups. This finding was also supported by microarray-based gene expression profiling in a subset of 35 patients. The expression of 37 genes differed significantly between the three groups defined by their expression of ZAP-70 and CD38, including genes that are involved in regulation of cell survival and chemotherapy resistance.
authors.affiliation: Department of Hematology and Oncology, Georg-August-University Goettingen, Germany. jan.duerig@uni-essen.de
authors.forename: R
authors.initials: R
authors.lastname: Schroers
authors.forename: F
authors.initials: F
authors.lastname: Griesinger
authors.forename: L
authors.initials: L
authors.lastname: Trümper
authors.forename: D
authors.initials: D
authors.lastname: Haase
authors.forename: B
authors.initials: B
authors.lastname: Kulle
authors.forename: L
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: L
authors.initials: L
authors.lastname: Sellmann
authors.forename: U
authors.initials: U
authors.lastname: Dührsen
authors.forename: J
authors.initials: J
authors.lastname: Dürig
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D002869:Chromosome Aberrations; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000032:analysis / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011237:Predictive Value of Tests; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D015203:Reproducibility of Results; D016019:Survival Analysis; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D015703:Antigens, CD; D007143:Immunoglobulin Heavy Chains; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1