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

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

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author
; ; ; ; ; ; ; and
organization
publishing date
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
2025-10-14 09:12:44
@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}},
}