Mutation analysis of the WT1 gene in sporadic childhood leukaemia

Algar, Elizabeth; Blackburn, Dana; Kromykh, T; Taylor, G; Smith, Peter J.

doi:10.1038/sj.leu.2400521

Cited by 28 publications

(18 citation statements)

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“…The present report is the ®rst to demonstrate that constitutive expression of WT1 in leukemic cell lines can lead to impairment of some di erentiation responses, suggesting that downregulation of WT1 indeed may be a prerequisite for terminal differentiation. WT1 antisense oligomers inhibit the cell growth of both leukemic cell lines and fresh leukemic cells from patients with acute or chronic myeloid leukemia, but not normal colony-forming-unit granulocyte-macrophage (CFU-GM) (Algar et al, 1996;Yamagami et al, 1996). This indicates that the WT1 protein may be important for the sustained proliferation of leukemic cells.…”

Section: Discussionmentioning

confidence: 99%

“…U937 clones expressing WT1 show similar growth rate and viability in suspension culture as control cells WT1 has been reported to in¯uence proliferation and viability of some cells Luo et al, 1995;Werner et al, 1995;Algar et al, 1996;Yamagami et al, 1996). Therefore, we determined the growth rate in suspension culture of the WT1(7KTS) and WT1(+KTS) transfected cells.…”

Section: Establishment and Characterization Of U937 Clones Constitutimentioning

confidence: 91%

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Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program

et al. 1998

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The Wilms tumor gene, WT1, encodes a zinc-®nger DNA binding protein which is thought to function as a tissue speci®c transcription factor, regulating cell growth and di erentiation. High expression of WT1 has been detected in a range of acute leukemias. To elucidate a role for WT1 in leukemogenesis, we transfected the monoblastic cell line U937, which lacks detectable levels of endogenous WT1, with two isoforms of WT1. We showed that, in contrast to U937 control cells, cells constitutively expressing either of the isoforms, WT1(7KTS) or WT1(+KTS), did not respond to di erentiation induction by retinoic acid or vitamin D3, as judged by the capacity to reduce nitro blue tetrazolium and morphology. Although U937 cells expressing WT1 were hampered in their ability to di erentiate on incubation with retinoic acid and vitamin D3, the induced G1/G0-accumulation was similar to di erentiating control cells treated with inducers. Furthermore, distinct e ects on the maturation process were indicated by downregulation of the myeloid cell surface makers CD13 and CD15, while the upregulation of CD14 and CD11c on WT1 transfected cells was similar to control cells upon incubation with retinoic acid and vitamin D3. Taken together our results demonstrate that a constitutive expression of WT1 in the leukemic cell line U937 leads to impairment of di erentiation responses, indicating that a high expression of WT1 can contribute to the di erentiation block of acute leukemia.

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Section: Discussionmentioning

confidence: 99%

Section: Establishment and Characterization Of U937 Clones Constitutimentioning

confidence: 91%

Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program

et al. 1998

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“…For these experiments, we chose two breast cancer cell lines that express different levels of endogenous WT1, a human leukemia cell line K562 that expresses high levels of WT1 and has previously been shown to undergo apoptosis when WT1 expression is blocked (Algar et al, 1996), and Cos-7 cells that have no WT1 expression. In our studies, we found that the c-myc promoter, especially a region between À107 and þ 36, is capable of responding to WT1 with increased expression in these cells.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional activation of c-myc proto-oncogene by WT1 protein

et al. 2004

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The Wilms' tumor 1 gene (WT1) plays an essential role in urogenital development and malignancy. Through DNA binding, WT1 can either enhance or repress transcription depending on the context of the DNA-binding sites or the cell type in which it is expressed. WT1 is overexpressed in a variety of human cancers, including leukemia and breast cancer; in these diseases, the expression of WT1 is associated with a poor prognosis. To determine how WT1 affects c-myc expression in the context of breast cancer cells, we have examined the ability of both endogenous and exogenous WT1 proteins in breast cancer cells to bind to the c-myc promoter in vivo. Using c-myc-promoterdriven luciferase constructs, we found that different forms of WT1 could enhance the expression of the reporter. Unlike other studies where WT1 is reported to be a negative regulator of c-myc, we found that both the À and þ KTS forms of WT1 could act to enhance c-myc expression, depending on the cell type. The WT1-binding site near the second major transcription start site of the cmyc promoter was confirmed to be involved in upregulation of human c-myc by WT1. Finally, we demonstrated that overexpression of WT1 induced a significant increase in the abundance of endogenous c-myc protein in breast cancer cells, consistent with the upregulation of c-myc transcription following WT1 induction. These observations strongly argue that in the case of breast cancer WT1 is functioning as an oncogene in part by stimulating the expression of c-myc.

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“…Exons 7-10 were amplified from gDNA using primers and conditions described in Algar et al 16 PCR products were gelpurified and subjected to direct sequencing using the ABI PRISM dideoxy terminator automated sequencing protocols of Applied Biosystems. Alternative splicing at the ϩ/Ϫ KTS site within exon 9 was examined using methods described previously.…”

Section: Mutation Analysismentioning

confidence: 99%

Expression and mutation analysis of the Wilms' tumor 1 gene in human neural tumors

Dennis

Manji

Carrington

et al. 2001

Intl Journal of Cancer

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The Wilms' tumor 1 gene, WT1, encodes a zinc-finger protein that is implicated in the development of Wilms' tumor. Mutant or aberrantly expressed WT1 isoforms have also been described in desmoplastic small round cell tumor, acute leukemias, mesothelioma, breast tumors and melanoma. During early development, WT1 is expressed in the brain and spinal cord, however its role in the malignancies that affect these tissues has not been previously investigated. In our study we have examined neural tumors including brain tumors and neuroblastomas for WT1 expression and for mutations affecting the zinc-fingers. Although WT1 expression was detected in gliomas, medulloblastomas and neuroblastomas, neither zinc-finger region mutations nor splicing anomalies affecting the KTS site were detected. We therefore conclude that WT1 does not play a significant role in the etiology of human neural tumors.

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Mutation analysis of the WT1 gene in sporadic childhood leukaemia

Abstract: Peripheral blood and bone marrow samples from patients less

Cited by 28 publications

References 1 publication

Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program

Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program

Transcriptional activation of c-myc proto-oncogene by WT1 protein

Expression and mutation analysis of the Wilms' tumor 1 gene in human neural tumors

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