Research Papers:

Role of ZNF224 in c-Myc repression and imatinib responsiveness in chronic myeloid leukemia

Gaetano Sodaro, Elena Cesaro, Giorgia Montano, Giancarlo Blasio, Federica Fiorentino, Simona Romano, Arnaud Jacquel, Patrick Aurberger and Paola Costanzo _

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Oncotarget. 2018; 9:3417-3431. https://doi.org/10.18632/oncotarget.23283

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Gaetano Sodaro1, Elena Cesaro1, Giorgia Montano2, Giancarlo Blasio1, Federica Fiorentino1, Simona Romano1, Arnaud Jacquel3, Patrick Aurberger3 and Paola Costanzo1

1Department of Molecular Medicine and Medical Biotechnology, University of Naples, Federico II, Naples 80131, Italy

2Department of Haematology and Transfusion Medicine, BioMedical Center, Lund University, Lund 22184, Sweden

3Université Côte d’Azur, Inserm, Nice 06204, France

Correspondence to:

Paola Costanzo, email: [email protected]

Keywords: ZNF224; chronic myeloid leukemia; c-Myc; imatinib; AG490

Abbreviations: CML: Chronic myelogenous leukemia; WT1: Wilms Tumor protein 1; TKIs: tyrosine kinase inhibitors; TSS: transcriptions start sites; ChIP: Chromatin immunoprecipitation assays

Received: July 26, 2017     Accepted: November 17, 2017     Published: December 15, 2017


The transcription factor ZNF224 plays a key proapoptotic role in chronic myelogenous leukemia (CML), by modulating Wilms Tumor protein 1 (WT1) dependent apoptotic genes transcription. Recently, we demonstrated that Bcr-Abl signaling represses ZNF224 expression in Bcr-Abl positive CML cell lines and in CML patients. Interestingly, Imatinib and second-generation tyrosine kinase inhibitors specifically increase ZNF224 expression.

On the other hand, Bcr-Abl positively modulates, via JAK2 activation, the expression of the c-Myc oncogene, which is required for Bcr-Abl oncogenic transformation in CML. Consequently, JAK2 inhibitors represent promising molecular therapeutic tools in CML.

In this work, we demonstrate that ZNF224 is a novel transcriptional repressor of c-Myc in CML. We also show that ZNF224 induction by Imatinib and AG490, a specific JAK2 inhibitor, is responsible for the transcriptional repression of c-MYC, thus highlighting the crucial role of the ZNF224/c-Myc axis in Imatinib responsiveness.

Interestingly, we also report that ZNF224 is induced by AG490 in Imatinib-resistant CML cells, leading to c-Myc repression and apoptosis induction. These findings suggest that the development of molecular tools able to induce ZNF224 expression could provide promising means to bypass Imatinib resistance in CML.

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