Sodaro, Gaetano (2017) THE REGULATORY ROLE OF THE TRANSCRIPTION FACTOR ZNF224 IN CHRONIC MYELOGENOUS LEUKEMIA. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: THE REGULATORY ROLE OF THE TRANSCRIPTION FACTOR ZNF224 IN CHRONIC MYELOGENOUS LEUKEMIA
Creators:
CreatorsEmail
Sodaro, Gaetanogaetano.sodaro@unina.it
Date: 8 April 2017
Number of Pages: 70
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 29
Coordinatore del Corso di dottorato:
nomeemail
Avvedimento, Vittorio Enricovittorioenrico.avvedimento@unina.it
Tutor:
nomeemail
Costanzo, PaolaUNSPECIFIED
Date: 8 April 2017
Number of Pages: 70
Uncontrolled Keywords: ZNF224; CHRONIC MYELOGENOUS LEUKEMIA; IMATINIB; IMTATINIB-RESISTANCE; C-MYC; AXL; TRANSCRIPTIONAL REPRESSION; AG490; APOPTOSIS;
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/10 - Biochimica
Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Date Deposited: 02 May 2017 14:03
Last Modified: 13 Mar 2018 11:27
URI: http://www.fedoa.unina.it/id/eprint/11646
DOI: 10.6093/UNINA/FEDOA/11646

Abstract

The transcription factor ZNF224 was recently identified as a proapoptotic factor in chronic myelogenous leukemia (CML), mediating ara-C drug- induced apoptosis. Most recently, we demonstrated that the fusion protein Bcr-Abl negatively regulates ZNF224 expression in CML, while Bcr-Abl inhibition by the tyrosine kinase inhibitor (TKI) Imatinib, used as first-line treatment in CML, triggers ZNF224 up-regulation in CML cells. On the other hand, Bcr-Abl via Jak2 activation increases the expression of c-Myc gene, which is required for Bcr-Abl oncogenic transformation in CML. Coherently, Bcr-Abl inhibition by Imatinib results in c-Myc reduction, which represents a key step for Imatinib and new generation TKIs responsiveness in CML. In this work, we demonstrated that ZNF224 is a novel transcriptional repressor of c-Myc oncogene in CML and coherently, hampers c-Myc proliferative network, reducing CML cells proliferation and DNA synthesis. Intriguingly, our data describe a crucial role for ZNF224 induction in Imatinib repression on c-Myc in CML and subsequently demonstrate that alterations in ZNF224 binding sites on c-Myc promoter significantly affect Imatinib transcriptional repression of c-Myc gene in CML cells, thus suggesting a potential implication of this region in Imatinib responsiveness. In addition, we further reveal that AG490, a potent Jak2 inhibitor, negatively regulate c-Myc, at least in part via ZNF224 up-regulation. A crucial problem linked to TKIs treatment in CML is the possibility to develop resistance towards these drugs. Here we demonstrate that ZNF224 expression is lower in Imatinib-resistant CML cells and that its induction by Imatinib is impaired, but can be restored by AG490. Consistently, AG490 treatment or ZNF224 induction in Imatinib-resistant CML cells results in c- Myc reduction and apoptosis induction. Moreover, enforcing ZNF224 implications in Imatinib responsiveness, we further demonstrate that ZNF224 is a transcriptional repressor of AXL tyrosine kinase in CML, which plays a crucial role in Imatinib resistance in CML. Taken together, our results identify new mechanisms by which ZNF224 transcription factor exerts an anti-oncogenic effect in CML and highlight the crucial role of ZNF224 in Imatinib responsiveness, thus providing convincing evidence that ZNF224 induction could play a role in overcoming Imatinib resistance in CML cells.

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