title: WT1-mediated repression of the proapoptotic transcription factor ZNF224 is triggered by the BCR-ABL oncogene.
abstract: The Kruppel-like protein ZNF224 is a co-factor of the Wilms' tumor 1 protein, WT1. We have previously shown that ZNF224 exerts a specific proapoptotic role in chronic myelogenous leukemia (CML) K562 cells and contributes to cytosine arabinoside-induced apoptosis, by modulating WT1-dependent transcription of apoptotic genes. Here we demonstrate that ZNF224 gene expression is down-regulated both in BCR-ABL positive cell lines and in primary CML samples and is restored after imatinib and second generation tyrosine kinase inhibitors treatment. We also show that WT1, whose expression is positively regulated by BCR-ABL, represses transcription of the ZNF224 gene. Finally, we report that ZNF224 is significantly down-regulated in patients with BCR-ABL positive chronic phase-CML showing poor response or resistance to imatinib treatment as compared to high-responder patients. Taken as a whole, our data disclose a novel pathway activated by BCR-ABL that leads to inhibition of apoptosis through the ZNF224 repression. ZNF224 could thus represent a novel promising therapeutic target in CML.
authors: Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II, Naples, Italy.|Department of Haematology and Transfusion Medicine, BioMedical Center, Lund University, Lund, Sweden.
authors: Giorgia
authors: G
authors: Montano
authors: Department of Haematology and Transfusion Medicine, BioMedical Center, Lund University, Lund, Sweden.
authors: Karina
authors: K
authors: Vidovic
authors: Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II, Naples, Italy.
authors: Chiara
authors: C
authors: Palladino
authors: Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II, Naples, Italy.
authors: Elena
authors: E
authors: Cesaro
authors: Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II, Naples, Italy.
authors: Gaetano
authors: G
authors: Sodaro
authors: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors: Concetta
authors: C
authors: Quintarelli
authors: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors: Biagio
authors: B
authors: De Angelis
authors: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors: Santa
authors: S
authors: Errichiello
authors: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors: Fabrizio
authors: F
authors: Pane
authors: Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II, Naples, Italy.
authors: Paola
authors: P
authors: Izzo
authors: Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II, Naples, Italy.
authors: Michela
authors: M
authors: Grosso
authors: Department of Haematology and Transfusion Medicine, BioMedical Center, Lund University, Lund, Sweden.
authors: Urban
authors: U
authors: Gullberg
authors: Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II, Naples, Italy.
authors: Paola
authors: P
authors: Costanzo
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; D025721:WT1 Proteins; C583751:WT1 protein, human; C470003:ZNF224 protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: BCR-ABL; WT1; ZNF224; chronic myeloid leukemia; tyrosine kinase inhibitors