title: Anti-apoptotic quinolinate phosphoribosyltransferase (QPRT) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells.
abstract: Wilms' tumor gene 1 (WT1) is a zinc finger transcription factor that has been implicated as an oncogene in leukemia and several other malignancies. When investigating possible gene expression network partners of WT1 in a large acute myeloid leukemia (AML) patient cohort, one of the genes with the highest correlation to WT1 was quinolinate phosphoribosyltransferase (QPRT), a key enzyme in the de novo nicotinamide adenine dinucleotide (NAD+) synthesis pathway. To investigate the possible relationship between WT1 and QPRT, we overexpressed WT1 in hematopoietic progenitor cells and cell lines, resulting in an increase of QPRT expression. WT1 knock-down gave a corresponding decrease in QPRT gene and protein expression. Chromatin-immunoprecipitation revealed WT1 binding to a conserved site in the first intron of the QPRT gene. Upon overexpression in leukemic K562 cells, QPRT conferred partial resistance to the anti-leukemic drug imatinib, indicating possible anti-apoptotic functions, consistent with previous reports on glioma cells. Interestingly, the rescue effect of QPRT overexpression was not correlated to increased NAD + levels, suggesting NAD + independent mechanisms. We conclude that QPRT, encoding a protein with anti-apoptotic properties, is a novel and direct target gene of WT1 in leukemic cells.
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Tove
authors.initials: T
authors.lastname: Ullmark
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Montano
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Linnea
authors.initials: L
authors.lastname: Järvstråt
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Jernmark Nilsson
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Håkansson
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Drott
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Karina
authors.initials: K
authors.lastname: Vidovic
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden. Electronic address: urban.gullberg@med.lu.se.
authors.forename: Urban
authors.initials: U
authors.lastname: Gullberg
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D016162:Genes, Wilms Tumor; D006801:Humans; D007438:Introns; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010430:Pentosyltransferases / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015533:Transcriptional Activation; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating)
chemical_list: D025721:WT1 Proteins; D009243:NAD; D010430:Pentosyltransferases; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating)
keywords: Acute myeloid leukemia; NAD+; Promoter; QPRT; Transcription; WT1