Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34+ progenitor cells

Svedberg, Helena; Richter, Johan; Gullberg, Urban

doi:10.1038/sj.leu.2402303

Cited by 29 publications

(32 citation statements)

References 42 publications

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“…Consistent with this observation was the finding that WT1 can repress the expression of cancer-related proteins such as c-myc, hTERT and bcl-2, and enhance the expression of antiproliferative proteins such as p21 in cell lines (Hewitt et al, 1995;Englert et al, 1997;Oh et al, 1999). Other evidence supporting the growth inhibitory effects of WT1 came from studies by Ellisen et al (2001) and Svedberg et al (2001), who introduced WT1 into normal hematopoietic progenitor cells. They found that forced expression of WT1 resulted in growth arrest and differentiation of the progenitor cells.…”

Section: Discussionmentioning

confidence: 87%

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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Section: Discussionmentioning

confidence: 87%

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

et al. 2004

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“…This result is compatible with previous reports from two other groups using human HSCs and progenitor cells. Gullberg and colleagues 46 demonstrated that WT1-A or WT1-B expression in human CD34 þ hematopoietic cells resulted in inhibition of proliferation. Haber and colleagues 47 reported that expression of WT1-B, and to a lesser extent WT1-A, in human CD34 þ CD38 À immature hematopoietic cells induced quiescence, and both WT1-A and WT1-B induced differentiation in myeloid progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

The Wilms’ tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis

et al. 2007

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The Wilms' tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1 GFP/ þ ) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (o1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ ETO þ TEL/PDGFbR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit þ lin À Sca-1 þ (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1 GFP/ þ mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.

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“…This observation did not correlate with any differences in cell cycle or viability. 24 Finally, overexpression of Wt1 in 32D cl3 cells, an IL-3-dependant myeloid progenitor murine cell line, blocked G-CSF induced differentiation of these cells in culture. 25 Several murine studies have been carried out to better characterize the role of Wt1 in normal hematopoiesis in vivo.…”

Section: Wt1 In Normal Hematopoiesismentioning

confidence: 97%

Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia

Rampal

Figueroa

2016

Haematologica

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IntroductionThe observations that the Wilms tumor 1 (WT1) protein is expressed in the majority of cases of acute myeloid leukemia (AML), and in addition, is mutated in a proportion of AML cases has led to extensive work over the last several decades to determine the mechanistic role of WT1 in AML. The fact that WT1 may be either overexpressed or mutated has given rise to the concept that it may act as both a tumor suppressor and oncogene, depending on the context. To date, much of the mechanistic work on WT1 has centered on its function as a transcription factor and the role of its many isoforms. However, more recent work stemming from largescale genomic studies in AML has revealed a new role for WT1 in epigenetic regulation. Indeed, work by several groups has demonstrated that WT1 appears to play a role along with TET proteins in mediating 5-hydroxymethylation of cytosines. These novel observations have given rise to an enhanced understanding of the complexity of this protein and its pathogenic role in leukemogenesis. Herein, we seek to review the major concepts and findings with regard to WT1 in oncogenesis and normal hematopoiesis, as well as any therapeutic strategies that may arise from these observations. WT structure and functionThe WT1 gene was initially identified as an inherited predisposition allele in probands with familial Wilms tumor.1,2 Numerous WT1 missense and nonsense mutations have been described in inherited and sporadic Wilms tumors, a pediatric malignancy affecting the kidneys.3,4 WT1 mutations are identified in approximately 20% of Wilms tumors, and are seen in patients with a familial disposition to these tumors. Wilms tumor is also associated with the Denys-Drash syndrome (DDS), encompassing Wilms tumor, congenital nephrotic syndrome, and XY pseudohermaphroditism, which results from point mutations in WT1. 5,6 Mutations in the intron 9 splice site have been identified in patients with Frasier syndrome, a developmental condition that affects kidneys and genitalia. 7 In addition, WT1 has been implicated in a number of other malignancies, including desmoplastic small cell tumor, breast cancer, retinoblastoma, and lung carcinoma. 8,9 In lung cancer, Wt1 has been shown to play a role in murine lung cancer models driven by Kras mutations where deletion or suppression of Wt1 resulted in senescence of primary murine cells expressing Kras, but had no effect on wild type cells. 10 Furthermore, loss of Wt1 led to decreased proliferation and tumor burden in Kras-driven lung carcinoma, © Ferrata Storti Foundation thus implicating Wt1 as a necessary component of Krasdriven oncogenesis. Taken together, these observations indicate that a spectrum of mutations in WT1 can lead to both inherited developmental syndromes and cancer predisposition.The WT1 protein contains an N-terminal transactivation domain and a C-terminus with four zinc-fingers that share DNA binding motifs with EGR1 1 (Figure 1). Four major WT1 isoforms result from differences in alternative splicing. These isoforms arise through...

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Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34+ progenitor cells

Cited by 29 publications

References 42 publications

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

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

The Wilms’ tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis

Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia

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