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: Giorgia Montano, Karina Vidovic, Chiara Palladino, Elena Cesaro, Gaetano Sodaro, Concetta Quintarelli, Biagio De Angelis, Santa Errichiello, Fabrizio Pane, Paola Izzo, Michela Grosso, Urban Gullberg, Paola Costanzo
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 29 Pg. 28223-37 (Sep 29 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26320177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Repressor Proteins
• WT1 Proteins
• WT1 protein, human
• ZNF224 protein, human
• Imatinib Mesylate
• Fusion Proteins, bcr-abl

Topics

• Apoptosis (genetics)
• Blotting, Western
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Fusion Proteins, bcr-abl (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• HEK293 Cells
• Humans
• Imatinib Mesylate (pharmacology)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics, metabolism, pathology)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• RNA Interference
• Repressor Proteins (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• WT1 Proteins (genetics, metabolism)