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

Oncotarget
Giorgia MontanoPaola Costanzo

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.

References

Mar 16, 2007·Leukemia·L YangM D Minden
Oct 2, 2008·Blood·Alfonso Quintás-Cardama, Jorge Cortes
Aug 28, 2009·Leukemia·M C MüllerA Hochhaus
Dec 17, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dragana Milojkovic, Jane Apperley
Jan 31, 2013·Human Molecular Genetics·Giorgia MontanoPaola Costanzo

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Citations

Jan 4, 2017·Human Molecular Genetics·Teresa BusielloElena Cesaro
Mar 7, 2021·International Journal of Molecular Sciences·Joanna SobocińskaUrszula Oleksiewicz
Jun 29, 2021·Human Molecular Genetics·Elena CesaroPaola Costanzo

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Methods Mentioned

BETA
flow cytometry
transfection
immunoprecipitation
PCR
ChIP
Assay
FACS

Software Mentioned

Sequence Detector

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

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