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Deregulation of the Wilms' tumour gene 1 protein (WT1) by BCR/ABL1 mediates resistance to imatinib in human leukaemia cells

Svensson, Emelie LU ; Vidovic, Karina LU ; Lassen, Carin LU ; Richter, Johan LU ; Olofsson, Tor LU ; Fioretos, Thoas LU and Gullberg, Urban LU (2007) In Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 21(12). p.2485-2494
Abstract
The Wilms' tumour gene 1 (WT1) protein is highly expressed in most leukaemias. Co-expression of WT1 and the fusion protein AML1-ETO in mice rapidly induces acute myeloid leukaemia (AML). Mechanisms behind expression of WT1, as well as consequences thereof, are still unclear. Here, we report that the fusion protein BCR/ABL1 increases expression of WT1 mRNA and protein via the phosphatidylinositol-3 kinase (PI3K)-Akt pathway. Inhibition of BCR/ABL1 or PI3K activity strongly suppressed transcription from WT1 promoter/enhancer reporters. Forced expression of BCR/ABL1 in normal human progenitor CD34+ cells increased WT1 mRNA and protein, further supporting the notion of BCR/ABL1-driven expression of WT1 in human haematopoietic cells. Forced... (More)
The Wilms' tumour gene 1 (WT1) protein is highly expressed in most leukaemias. Co-expression of WT1 and the fusion protein AML1-ETO in mice rapidly induces acute myeloid leukaemia (AML). Mechanisms behind expression of WT1, as well as consequences thereof, are still unclear. Here, we report that the fusion protein BCR/ABL1 increases expression of WT1 mRNA and protein via the phosphatidylinositol-3 kinase (PI3K)-Akt pathway. Inhibition of BCR/ABL1 or PI3K activity strongly suppressed transcription from WT1 promoter/enhancer reporters. Forced expression of BCR/ABL1 in normal human progenitor CD34+ cells increased WT1 mRNA and protein, further supporting the notion of BCR/ABL1-driven expression of WT1 in human haematopoietic cells. Forced expression of WT1 in K562 cells provided protection against cytotoxic effects of the ABL1 tyrosine kinase inhibitor imatinib, as judged by effects on viability measured by trypan blue exclusion, metabolic activity, annexin V and DAPI (4', 6-diamidino-2-phenylindole) staining. None of the isoforms provided any detectable protection against apoptosis induced by arsenic trioxide and only very weak protection against etoposide, indicating that WT1 interferes with specific apoptotic signalling pathways. Our data demonstrate that WT1 expression is induced by oncogenic signalling from BCR/ABL1 and that WT1 contributes to resistance against apoptosis induced by imatinib. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
volume
21
issue
12
pages
2485 - 2494
publisher
Nature Publishing Group
external identifiers
  • pmid:17728783
  • wos:000251139500013
  • scopus:36348970549
ISSN
1476-5551
DOI
10.1038/sj.leu.2404924
language
English
LU publication?
yes
id
6a92a33b-ac00-45ff-b3c9-cde54dbc64d4 (old id 1138961)
date added to LUP
2008-08-19 15:56:52
date last changed
2017-08-06 04:53:36
@article{6a92a33b-ac00-45ff-b3c9-cde54dbc64d4,
  abstract     = {The Wilms' tumour gene 1 (WT1) protein is highly expressed in most leukaemias. Co-expression of WT1 and the fusion protein AML1-ETO in mice rapidly induces acute myeloid leukaemia (AML). Mechanisms behind expression of WT1, as well as consequences thereof, are still unclear. Here, we report that the fusion protein BCR/ABL1 increases expression of WT1 mRNA and protein via the phosphatidylinositol-3 kinase (PI3K)-Akt pathway. Inhibition of BCR/ABL1 or PI3K activity strongly suppressed transcription from WT1 promoter/enhancer reporters. Forced expression of BCR/ABL1 in normal human progenitor CD34+ cells increased WT1 mRNA and protein, further supporting the notion of BCR/ABL1-driven expression of WT1 in human haematopoietic cells. Forced expression of WT1 in K562 cells provided protection against cytotoxic effects of the ABL1 tyrosine kinase inhibitor imatinib, as judged by effects on viability measured by trypan blue exclusion, metabolic activity, annexin V and DAPI (4', 6-diamidino-2-phenylindole) staining. None of the isoforms provided any detectable protection against apoptosis induced by arsenic trioxide and only very weak protection against etoposide, indicating that WT1 interferes with specific apoptotic signalling pathways. Our data demonstrate that WT1 expression is induced by oncogenic signalling from BCR/ABL1 and that WT1 contributes to resistance against apoptosis induced by imatinib.},
  author       = {Svensson, Emelie and Vidovic, Karina and Lassen, Carin and Richter, Johan and Olofsson, Tor and Fioretos, Thoas and Gullberg, Urban},
  issn         = {1476-5551},
  language     = {eng},
  number       = {12},
  pages        = {2485--2494},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K},
  title        = {Deregulation of the Wilms' tumour gene 1 protein (WT1) by BCR/ABL1 mediates resistance to imatinib in human leukaemia cells},
  url          = {http://dx.doi.org/10.1038/sj.leu.2404924},
  volume       = {21},
  year         = {2007},
}