title: Expression of nucleoside-metabolizing enzymes in myelodysplastic syndromes and modulation of response to azacitidine.
abstract: The nucleoside analog azacitidine (AZA) is used in the treatment of myelodysplastic syndromes (MDS), but 30-40% of patients fail to respond or relapse after treatment. Hence, to identify new molecular alterations that allow for identification of patients unlikely to respond to AZA could impact the utility of this therapy. We determined the expression levels of genes involved in AZA metabolism: UCK1, UCK2, DCK, hENT1, RRM1 and RRM2 using quantitative PCR in samples from 57 patients with MDS who received AZA. Lower expression of UCK1 was seen in patients without a response to AZA (median 0.2 vs 0.49 for patients with response to AZA, P=0.07). This difference in UCK1 expression was not influenced by aberrant methylation of the UCK1 promoter. In addition, the seven polymorphic loci found in the coding sequence were not associated with UCK1 gene expression nor AZA response. Silencing of UCK1 by siRNA leads to blunted response to AZA in vitro. The univariate analysis revealed that patients expressing lower than median levels of UCK1 had a shorter overall survival (P=0.049). Our results suggest that expression level of UCK1 is correlated with clinical outcome and may influence the clinical response to AZA treatment in patients with MDS.
authors.affiliation: Department of Hematology, Università degli Studi di Firenze, AOU Careggi, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Department of Hematology, Università degli Studi di Firenze, AOU Careggi, Florence, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Masala
authors.affiliation: Department of Hematology, Università degli Studi di Firenze, AOU Careggi, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.affiliation: German Cancer Research Center, Genomic Epidemiology Group, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Martino
authors.affiliation: Department of Hematology, Università degli Studi di Firenze, AOU Careggi, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sanna
authors.affiliation: Department of Hematology, Università degli Studi di Firenze, AOU Careggi, Florence, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Buchi
authors.affiliation: German Cancer Research Center, Genomic Epidemiology Group, Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Canzian
authors.affiliation: Department of Clinical and Biological Sciences, Università di Torino, Turin, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Cilloni
authors.affiliation: Department of Clinical and Biological Sciences, Università di Torino, Turin, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Gaidano
authors.affiliation: Department of Hematology, Università Cattolica S. Cuore, Rome, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Voso
authors.affiliation: 1] Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France [2] Département Développement, Reproduction et Cancer, Institut Cochin, INSERM U1016, CNRS UMR8104 and Université Paris Descartes, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Kosmider
authors.affiliation: 1] Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France [2] Département Développement, Reproduction et Cancer, Institut Cochin, INSERM U1016, CNRS UMR8104 and Université Paris Descartes, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Fontenay
authors.affiliation: Department of Hematology, Università degli Studi di Firenze, AOU Careggi, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gozzini
authors.affiliation: Department of Hematology, Università degli Studi di Firenze, AOU Careggi, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bosi
authors.affiliation: Department of Hematology, Università degli Studi di Firenze, AOU Careggi, Florence, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Santini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001374:Azacitidine / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000201:enzymology*; D009705:Nucleosides / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011379:Prognosis
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004798:Enzymes; D009705:Nucleosides; D001374:Azacitidine