Role of ZNF224 in c-Myc repression and imatinib responsiveness in chronic myeloid leukemia
(2018) In Oncotarget 9(3). p.3417-3431- Abstract
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... (More)
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 Imatinibresistant 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.
(Less)
- author
- Sodaro, Gaetano ; Cesaro, Elena ; Montano, Giorgia LU ; Blasio, Giancarlo ; Fiorentino, Federica ; Romano, Simona ; Jacquel, Arnaud ; Aurberger, Patrick and Costanzo, Paola
- organization
- publishing date
- 2018
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- AG490, C-Myc, Chronic myeloid leukemia, Imatinib, ZNF224
- in
- Oncotarget
- volume
- 9
- issue
- 3
- pages
- 15 pages
- publisher
- Impact Journals
- external identifiers
-
- scopus:85040185282
- pmid:29423056
- ISSN
- 1949-2553
- DOI
- 10.18632/oncotarget.23283
- language
- English
- LU publication?
- yes
- id
- 78ea834e-3c55-494d-bbb6-43438439a6b5
- date added to LUP
- 2018-01-24 14:50:18
- date last changed
- 2024-05-13 04:26:09
@article{78ea834e-3c55-494d-bbb6-43438439a6b5,
abstract = {{<p>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 Imatinibresistant 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.</p>}},
author = {{Sodaro, Gaetano and Cesaro, Elena and Montano, Giorgia and Blasio, Giancarlo and Fiorentino, Federica and Romano, Simona and Jacquel, Arnaud and Aurberger, Patrick and Costanzo, Paola}},
issn = {{1949-2553}},
keywords = {{AG490; C-Myc; Chronic myeloid leukemia; Imatinib; ZNF224}},
language = {{eng}},
number = {{3}},
pages = {{3417--3431}},
publisher = {{Impact Journals}},
series = {{Oncotarget}},
title = {{Role of ZNF224 in c-Myc repression and imatinib responsiveness in chronic myeloid leukemia}},
url = {{http://dx.doi.org/10.18632/oncotarget.23283}},
doi = {{10.18632/oncotarget.23283}},
volume = {{9}},
year = {{2018}},
}