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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
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, LLC
external identifiers
  • scopus:85040185282
ISSN
1949-2553
DOI
language
English
LU publication?
yes
id
78ea834e-3c55-494d-bbb6-43438439a6b5
date added to LUP
2018-01-24 14:50:18
date last changed
2018-05-29 11:13:33
@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},
  keyword      = {AG490,C-Myc,Chronic myeloid leukemia,Imatinib,ZNF224},
  language     = {eng},
  number       = {3},
  pages        = {3417--3431},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {Role of ZNF224 in c-Myc repression and imatinib responsiveness in chronic myeloid leukemia},
  url          = {http://dx.doi.org/},
  volume       = {9},
  year         = {2018},
}