Overexpression of murine WT1+/+ and −/− isoforms has no effect on chemoresistance but delays differentiation in the K562 leukemia cell line

Carrington, Darryl P.; Algar, Elizabeth

doi:10.1016/s0145-2126(00)00064-3

Cited by 15 publications

(12 citation statements)

References 40 publications

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“…In consistence with this notion, WT1 overexpression did not alter induction of apoptosis in K562 cells induced by cisplatin or adriamycin. 54 Very recently, it was reported that imatinib-induced killing of CML cells is mediated by upregulation of Bim and Bad. 55 It remains to be investigated whether WT1 affects other bcl-2 family members than bcl-2 in imatinibtreated CML cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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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 þ 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 0 , 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…In hematopoietic malignancy, WT1 is overexpressed in a majority of acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), correlated to poor clinical outcome (7)(8)(9)(10). WT1 interferes with differentiation of leukemic cell lines (11)(12)(13) and in mice, WT1 cooperates with the leukemia fusion protein AML1-ETO (RUNX1/RUNX1T1) to rapidly induce leukemia (14). Also various types of solid cancers show over-expression of WT1 (15).…”

Section: Introductionmentioning

confidence: 99%

Anti-apoptotic quinolinate phosphoribosyltransferase ( QPRT ) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells

Ullmark

Montano

Järvstråt

et al. 2017

Biochemical and Biophysical Research Communications

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“…In HL-60 and K562 cells, the wt1 expression correlates with the degree of vincristine resistance 24 but not with cisplatin or doxorubicin resistance in K562 cells. 25 WT1 also regulates the antiapoptotic gene bcl-2, which might be involved in resistance to chemotherapy. 3 These data indicate the important function of wt1 for leukemic cell growth and survival and that the removal may have an antileukemic and chemotherapy-supporting effect.…”

Section: Introductionmentioning

confidence: 99%

Effective treatment of leukemic cell lines with wt1 siRNA

et al. 2007

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The expression of wt1 and bcl-2 is considered to have a proliferating and survival supporting effect in leukemia blast cells. Here we describe the use of siRNA against wt1 and bcl-2 in leukemic cell lines for successful growth inhibition. We have used two different sequences designated as siRNA-A and siRNA-B corresponding to positions within the wt1 coding sequence to downregulate wt1 and a commercially available siRNA kit to downregulate bcl-2. WT1 and bcl-2 gene expression in transfected leukemic cell lines were evaluated with RT-PCR and western blot analyses. MTT assay was used to measure the cell viability and flow cytometry using annexin V/PI-staining for apoptosis. K562 and HL-60 cell lines transfected with siRNA-A targeted to wt1 had greatly decreased levels of both wt1 mRNA and protein expression. In contrast, siRNA-B and control siRNA led almost to no effect on wt1 mRNA and protein expression. siRNA-A-reduced wt1 mRNA expression was associated with a decreased cell proliferation and increased number of apoptotic cells in K562 and HL-60 cells by 24 and 48 h after transfection. Combined treatment with wt1 siRNA and bcl-2 siRNA simultaneously was not able to override the cell growth and apoptosis effects compared to single treatment with wt1 siRNA. siRNAs targeted against human wt1 might be a valuable tool as antiproliferative agent against wt1 expressing leukemic cells.

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Overexpression of murine WT1+/+ and −/− isoforms has no effect on chemoresistance but delays differentiation in the K562 leukemia cell line

Cited by 15 publications

References 40 publications

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

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

Anti-apoptotic quinolinate phosphoribosyltransferase ( QPRT ) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells

Effective treatment of leukemic cell lines with wt1 siRNA

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