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The hematopoietic tumor suppressor interferon regulatory factor 8 (IRF8) is upregulated by the antimetabolite cytarabine in leukemic cells involving the zinc finger protein ZNF224, acting as a cofactor of the Wilms' tumor gene 1 (WT1) protein.

Montano, Giorgia LU ; Ullmark, Tove LU ; Jernmark Nilsson, Helena LU ; Sodaro, Gaetano; Drott, Kristina LU ; Costanzo, Paola; Vidovic, Karina LU and Gullberg, Urban LU (2016) In Leukemia Research: A Forum for Studies on Leukemia and Normal Hemopoiesis 40(1). p.60-67
Abstract
The transcription factor interferon regulatory factor-8 (IRF8) is highly expressed in myeloid progenitors, while most myeloid leukemias show low or absent expression. Loss of IRF8 in mice leads to a myeloproliferative disorder, indicating a tumor-suppressive role of IRF8. The Wilms tumor gene 1 (WT1) protein represses the IRF8-promoter. The zinc finger protein ZNF224 can act as a transcriptional co-factor of WT1 and potentiate the cytotoxic response to the cytostatic drug cytarabine. We hypothesized that cytarabine upregulates IRF8 and that transcriptional control of IRF8 involves WT1 and ZNF224. Treatment of leukemic K562 cells with cytarabine upregulated IRF8 protein and mRNA, which was correlated to increased expression of ZNF224. Knock... (More)
The transcription factor interferon regulatory factor-8 (IRF8) is highly expressed in myeloid progenitors, while most myeloid leukemias show low or absent expression. Loss of IRF8 in mice leads to a myeloproliferative disorder, indicating a tumor-suppressive role of IRF8. The Wilms tumor gene 1 (WT1) protein represses the IRF8-promoter. The zinc finger protein ZNF224 can act as a transcriptional co-factor of WT1 and potentiate the cytotoxic response to the cytostatic drug cytarabine. We hypothesized that cytarabine upregulates IRF8 and that transcriptional control of IRF8 involves WT1 and ZNF224. Treatment of leukemic K562 cells with cytarabine upregulated IRF8 protein and mRNA, which was correlated to increased expression of ZNF224. Knock down of ZNF224 with shRNA suppressed both basal and cytarabine-induced IRF8 expression. While ZNF224 alone did not affect IRF8 promoter activity, ZNF224 partially reversed the suppressive effect of WT1 on the IRF8 promoter, as judged by luciferase reporter experiments. Coprecipitation revealed nuclear binding of WT1 and ZNF224, and by chromatin immunoprecipitation (ChIP) experiments it was demonstrated that WT1 recruits ZNF224 to the IRF8 promoter. We conclude that cytarabine-induced upregulation of the IRF8 in leukemic cells involves increased levels of ZNF224, which can counteract the repressive activity of WT1 on the IRF8-promoter. (Less)
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author
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Contribution to journal
publication status
published
subject
in
Leukemia Research: A Forum for Studies on Leukemia and Normal Hemopoiesis
volume
40
issue
1
pages
60 - 67
publisher
Elsevier
external identifiers
  • pmid:26563595
  • wos:000367237000010
  • scopus:84961763243
ISSN
1873-5835
DOI
10.1016/j.leukres.2015.10.014
language
English
LU publication?
yes
id
67e8579d-da77-4409-bf13-2b8cda595a09 (old id 8235686)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26563595?dopt=Abstract
date added to LUP
2015-12-04 21:21:00
date last changed
2017-10-29 03:13:12
@article{67e8579d-da77-4409-bf13-2b8cda595a09,
  abstract     = {The transcription factor interferon regulatory factor-8 (IRF8) is highly expressed in myeloid progenitors, while most myeloid leukemias show low or absent expression. Loss of IRF8 in mice leads to a myeloproliferative disorder, indicating a tumor-suppressive role of IRF8. The Wilms tumor gene 1 (WT1) protein represses the IRF8-promoter. The zinc finger protein ZNF224 can act as a transcriptional co-factor of WT1 and potentiate the cytotoxic response to the cytostatic drug cytarabine. We hypothesized that cytarabine upregulates IRF8 and that transcriptional control of IRF8 involves WT1 and ZNF224. Treatment of leukemic K562 cells with cytarabine upregulated IRF8 protein and mRNA, which was correlated to increased expression of ZNF224. Knock down of ZNF224 with shRNA suppressed both basal and cytarabine-induced IRF8 expression. While ZNF224 alone did not affect IRF8 promoter activity, ZNF224 partially reversed the suppressive effect of WT1 on the IRF8 promoter, as judged by luciferase reporter experiments. Coprecipitation revealed nuclear binding of WT1 and ZNF224, and by chromatin immunoprecipitation (ChIP) experiments it was demonstrated that WT1 recruits ZNF224 to the IRF8 promoter. We conclude that cytarabine-induced upregulation of the IRF8 in leukemic cells involves increased levels of ZNF224, which can counteract the repressive activity of WT1 on the IRF8-promoter.},
  author       = {Montano, Giorgia and Ullmark, Tove and Jernmark Nilsson, Helena and Sodaro, Gaetano and Drott, Kristina and Costanzo, Paola and Vidovic, Karina and Gullberg, Urban},
  issn         = {1873-5835},
  language     = {eng},
  number       = {1},
  pages        = {60--67},
  publisher    = {Elsevier},
  series       = {Leukemia Research: A Forum for Studies on Leukemia and Normal Hemopoiesis},
  title        = {The hematopoietic tumor suppressor interferon regulatory factor 8 (IRF8) is upregulated by the antimetabolite cytarabine in leukemic cells involving the zinc finger protein ZNF224, acting as a cofactor of the Wilms' tumor gene 1 (WT1) protein.},
  url          = {http://dx.doi.org/10.1016/j.leukres.2015.10.014},
  volume       = {40},
  year         = {2016},
}