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 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 Imatinib-resistant 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.
Highlights
The chimeric Bcr-Abl fusion oncoprotein is a product of a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22 t(9;22)(q34;q11) [1] and exerts a critical role in chronic myelogenous leukemia (CML) pathogenesis [2,3,4]
Our previous findings demonstrated that Bcr-Abl fusion protein negatively regulates the expression of the pro-apoptotic transcription factor ZNF224 in CML and Bcr-Abl inhibition by Imatinib and secondgeneration tyrosine kinase inhibitors (TKIs) Dasatinib and Nilotinib increase ZNF224 expression [25]
To assess whether c-Myc promoter activity was affected by ZNF224 and to investigate the regions of c-Myc promoter involved in this regulation, we introduced three luciferase reporter plasmids containing progressive deletions of the c-Myc promoter (Figure 1B, lower panel) into HEK293 cells in the presence of increasing amounts of a ZNF224 expression vector; as shown in Figure 1C, c-Myc promoter transcriptional activity was progressively decreased by ZNF224 overexpression in all the three deletion mutants, indicating that ZNF224 represses c-Myc gene through the binding at the high regulatory P2 region of the c-Myc promoter, that is included in the DEL-6 construct
Summary
The chimeric Bcr-Abl fusion oncoprotein is a product of a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22 t(9;22)(q34;q11) [1] and exerts a critical role in chronic myelogenous leukemia (CML) pathogenesis [2,3,4]. Constitutive tyrosine kinase activity of Bcr-Abl causes the activation of a multitude of signaling pathways, including Jak/STAT [5], PI3K/Akt [6, 7], Ras [8] and NFkB [9], which eventually lead to the induction of several oncogenic transcription factors, important for sustaining cellular transformation in CML. The inhibition of Bcr-Abl tyrosine kinase activity by Imatinib strongly reduces c-Myc expression and hematopoietic tumoral features of CML cells. In agreement with the JAK2 role in mediating Bcr-Abl induction of c-Myc, JAK2 kinase inhibitors, such as AG490, strongly reduce c-Myc expression in CML and induce apoptosis [14, 16], indicating JAK2 pathway as an important therapeutic target to overcome Imatinib resistance in CML, a crucial issue in clinical practice [17,18,19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
