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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 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.

Detaljer

Författare
  • Gaetano Sodaro
  • Elena Cesaro
  • Giorgia Montano
  • Giancarlo Blasio
  • Federica Fiorentino
  • Simona Romano
  • Arnaud Jacquel
  • Patrick Aurberger
  • Paola Costanzo
Enheter & grupper
Externa organisationer
  • University of Naples Federico II
  • Institut Gustave Roussy
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi

Nyckelord

Originalspråkengelska
Sidor (från-till)3417-3431
Antal sidor15
TidskriftOncotarget
Volym9
Utgåva nummer3
StatusPublished - 2018
PublikationskategoriForskning
Peer review utfördJa