title: Overexpression of uridine diphospho glucuronosyltransferase 2B17 in high-risk chronic lymphocytic leukemia.
abstract: Uridine diphospho glucuronosyltransferase 2B17 (UGT2B17) glucuronidates androgens and xenobiotics including certain drugs. The UGT2B17 gene shows a remarkable copy number variation (CNV), which predisposes for solid tumors and influences drug response. Here, we identify a yet undescribed UGT2B17 mRNA overexpression in poor-risk chronic lymphocytic leukemia (CLL). In total, 320 CLL patients and 449 healthy donors were analyzed. High (above median) UGT2B17 expression was associated with established CLL poor prognostic factors and resulted in shorter treatment-free and overall survival (hazard ratio ([death] 2.18; 95% CI 1.18-4.01; P = .013). The prognostic impact of mRNA expression was more significant than that of UGT2B17 CNV. UGT2B17 mRNA levels in primary CLL samples directly correlated with functional glucuronidation activity toward androgens and the anticancer drug vorinostat (R > 0.9, P < .001). After treatment with fludarabine containing regimens UGT2B17 was up-regulated particularly in poor responders (P = .030). We observed an exclusive involvement of the 2B17 isoform within the UGT protein family. Gene expression profiling of a stable UGT2B17 knockdown in the CLL cell line MEC-1 demonstrated a significant involvement in key cellular processes. These findings establish a relevant role of UGT2B17 in CLL with functional consequences and potential therapeutic implications.
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Gruber
authors.forename: Judith
authors.initials: J
authors.lastname: Bellemare
authors.forename: Gregor
authors.initials: G
authors.lastname: Hoermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Gleiss
authors.forename: Edit
authors.initials: E
authors.lastname: Porpaczy
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Trang
authors.initials: T
authors.lastname: Le
authors.forename: Sonja
authors.initials: S
authors.lastname: Zehetmayer
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
authors.forename: Alexander
authors.initials: A
authors.lastname: Gaiger
authors.forename: Medhat
authors.initials: M
authors.lastname: Shehata
authors.forename: Karin
authors.initials: K
authors.lastname: Fleiss
authors.forename: Cathrin
authors.initials: C
authors.lastname: Skrabs
authors.forename: Éric
authors.initials: É
authors.lastname: Lévesque
authors.forename: Katrina
authors.initials: K
authors.lastname: Vanura
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaeger
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage; D055785:Gene Knockdown Techniques; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012307:Risk Factors; D059467:Transcriptome; D015854:Up-Regulation / Q000187:drug effects; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human; D014740:Vidarabine; C024352:fludarabine