Oncotarget

Research Papers:

WT1-mediated repression of the proapoptotic transcription factor ZNF224 is triggered by the BCR-ABL oncogene

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 and Paola Costanzo _

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Oncotarget. 2015; 6:28223-28237. https://doi.org/10.18632/oncotarget.4950

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Abstract

Giorgia Montano1,2, Karina Vidovic2, Chiara Palladino1, Elena Cesaro1, Gaetano Sodaro1, Concetta Quintarelli3, Biagio De Angelis3, Santa Errichiello3, Fabrizio Pane3, Paola Izzo1, Michela Grosso1, Urban Gullberg2 and Paola Costanzo1

1 Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II, Naples, Italy

2 Department of Haematology and Transfusion Medicine, BioMedical Center, Lund University, Lund, Sweden

3 Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

Correspondence to:

Paola Costanzo, email:

Keywords: ZNF224, chronic myeloid leukemia, BCR-ABL, WT1, tyrosine kinase inhibitors

Received: March 23, 2015 Accepted: July 08, 2015 Published: July 22, 2015

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.


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