title: Progranulin is a novel independent predictor of disease progression and overall survival in chronic lymphocytic leukemia.
abstract: Progranulin (Pgrn) is a 88 kDa secreted protein with pleiotropic functions including regulation of cell cycle progression, cell motility, wound repair and tumorigenesis. Using microarray based gene expression profiling we have recently demonstrated that the gene for Pgrn, granulin (GRN), is significantly higher expressed in aggressive CD38(+)ZAP-70(+) as compared to indolent CD38(-)ZAP-70(-) chronic lymphocytic leukemia (CLL) cases. Here, we measured Pgrn plasma concentrations by enzyme-linked immunosorbent assay (ELISA) in the Essen CLL cohort of 131 patients and examined Pgrn for association with established prognostic markers and clinical outcome. We found that high Pgrn plasma levels were strongly associated with adverse risk factors including unmutated IGHV status, expression of CD38 and ZAP-70, poor risk cytogenetics (11q-, 17p-) as detected by flourescence in situ hybridization (FISH) and high Binet stage. Pgrn as well as the aforementioned risk factors were prognostic for time to first treatment and overall survival in this series. Importantly, these results could be confirmed in the independent multicentric CLL1 cohort of untreated Binet stage A patients (n = 163). Here, multivariate analysis of time to first treatment revealed that high risk Pgrn (HR = 2.06, 95%-CI = 1.13-3.76, p = 0.018), unmutated IGHV status (HR = 5.63, 95%-CI = 3.05-10.38, p<0.001), high risk as defined by the study protocol (HR = 2.06, 95%-CI = 1.09-3.89, p = 0.026) but not poor risk cytogenetics were independent prognostic markers. In summary our results suggest that Pgrn is a novel, robust and independent prognostic marker in CLL that can be easily measured by ELISA.
authors.affiliation: Department of Hematology, University Hospital, University of Duisburg-Essen, Essen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Göbel
authors.forename: Lewin
authors.initials: L
authors.lastname: Eisele
authors.forename: Michael
authors.initials: M
authors.lastname: Möllmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Hüttmann
authors.forename: Patricia
authors.initials: P
authors.lastname: Johansson
authors.forename: René
authors.initials: R
authors.lastname: Scholtysik
authors.forename: Manuela
authors.initials: M
authors.lastname: Bergmann
authors.forename: Raymonde
authors.initials: R
authors.lastname: Busch
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Till
authors.initials: T
authors.lastname: Seiler
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.forename: Jan
authors.initials: J
authors.lastname: Dürig
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D011379:Prognosis; D000077153:Progranulins
chemical_list: D014408:Biomarkers, Tumor; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins