Very low frequencies of human normal CD34<sup>+</sup> haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells

Hosen, Naoki; Sonoda, Yoshiaki; Oji, Yusuke; Kimura, Takafumi; Minamiguchi, Hitoshi; Tamaki, Hiroya; Kawakami, Manabu; Asada, Masaki; Kanato, Keisuke; Motomura, Mari; Murakami, Masaki; Fujioka, Tatsuya; Masuda, Takayuki; Kim, Eui Ho; Tsuboi, Akihiro; Oka, Y.; Soma, Toshihiro; Ogawa, Hiroyasu; Sugiyama, Haruo

doi:10.1046/j.1365-2141.2002.03261.x

Cited by 101 publications

(72 citation statements)

References 51 publications

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“…As to the WT1 mRNA of the stem cell fraction, Hosen et al 31 described the very low frequency of normal CD34-positivehematopoietic progenitor cells with WT1 mRNA level similar to those in leukemia cells. Our current study supports their results.…”

Section: Gata-mentioning

confidence: 99%

GATA-1 and GATA-2 binding to 3′ enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines

et al. 2009

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Although oncogenic functions and the clinical significance of Wilms tumor 1 (WT1) have been extensively studied in acute leukemia, the regulatory mechanism of its transcription still remains to be determined. We found a significant correlation among the amounts of WT1, GATA-1 and GATA-2 mRNAs from leukemia and solid tumor cell lines. Overexpression and small interfering RNA (siRNA) transfection experiments of GATA-1 and GATA-2 showed that these GATA transcription factors could induce WT1 expression. Promoter analysis showed that the 5 0 promoter did not explain the different WT1 mRNA levels between cell lines. The 3 0 enhancer, especially the distal sites out of six putative GATA binding sites located within the region, but not the intron 3 enhancer, were essential for the WT1 mRNA level. Electrophoretic mobility shift assay (EMSA) showed both GATA-1 and GATA-2 bound to these GATA sites. Besides acute leukemia cell lines, solid tumor cell lines including, TYK-nu-cPr also showed a high level of WT1 mRNA. We showed that GATA-2 expression is a determinant of WT1 mRNA expression in both TYK-nu-cPr cells and HL60 cells without GATA-1 expression. Taken together, these results suggest that GATA-1 and/or GATA-2 binding to a GATA site of the 3 0 enhancer of WT1 played an important role in WT1 gene expression.

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Section: Gata-mentioning

confidence: 99%

GATA-1 and GATA-2 binding to 3′ enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines

et al. 2009

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“…[20][21][22] Except for very early investigations, 4 WT1 expression has been identified in normal BM and PSC controls or CD34 þ concentrates in all further studies, either in a proportion 25,37,39,42 or all 30,43,44 of the samples tested. In agreement with the latter studies, we could detect WT1 expression in all analyzed normal BM and PSC samples.…”

Section: Wilms' Tumor Gene 1 (Wt1) Expression L Boublikova Et Almentioning

confidence: 99%

“…Hematopoietic precursors show transient biphasic WT1 overexpression, which has a stage-specific effect: WT1 maintains primitive stem cells in a quiescent state, while it promotes differentiation of more mature lineage-committed progenitors. [20][21][22] Alterations of WT1 expression (both under-or overexpression) have been described in a number of malignancies and premalignant syndromes. Remarkably, WT1 overexpression has been found in 80-90% of acute myeloid leukemia (AML) and 70-90% of acute lymphoblastic leukemia (ALL) patients, with an even higher frequency at relapse.…”

Section: Introductionmentioning

confidence: 99%

Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring

et al. 2005

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Wilms' tumor gene 1 (WT1) is overexpressed in the majority (70-90%) of acute leukemias and has been identified as an independent adverse prognostic factor, a convenient minimal residual disease (MRD) marker and potential therapeutic target in acute leukemia. We examined WT1 expression patterns in childhood acute lymphoblastic leukemia (ALL), where its clinical implication remains unclear. Using a real-time quantitative PCR designed according to Europe Against Cancer Program recommendations, we evaluated WT1 expression in 125 consecutively enrolled patients with childhood ALL (106 BCP-ALL, 19 T-ALL) and compared it with physiologic WT1 expression in normal and regenerating bone marrow (BM). In childhood B-cell precursor (BCP)-ALL, we detected a wide range of WT1 levels (5 logs) with a median WT1 expression close to that of normal BM. WT1 expression in childhood T-ALL was significantly higher than in BCP-ALL (Po0.001). Patients with MLL-AF4 translocation showed high WT1 overexpression (Po0.01) compared to patients with other or no chromosomal aberrations. Older children (X10 years) expressed higher WT1 levels than children under 10 years of age (Po0.001), while there was no difference in WT1 expression in patients with peripheral blood leukocyte count (WBC) X50 Â 10 9 /l and lower. Analysis of relapsed cases (14/125) indicated that an abnormal increase or decrease in WT1 expression was associated with a significantly increased risk of relapse (P ¼ 0.0006), and this prognostic impact of WT1 was independent of other main risk factors (P ¼ 0.0012). In summary, our study suggests that WT1 expression in childhood ALL is very variable and much lower than in AML or adult ALL. WT1, thus, will not be a useful marker for MRD detection in childhood ALL, however, it does represent a potential independent risk factor in childhood ALL. Interestingly, a proportion of childhood ALL patients express WT1 at levels below the normal physiological BM WT1 expression, and this reduced WT1 expression appears to be associated with a higher risk of relapse.

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“…We previously reported that only 1.2% of normal human CD34 þ hematopoietic progenitor cells express WT1, and both CD34 þ CD38 À and CD34 þ CD38 þ bone marrow (BM) cells contain WT1-expressing cells at similar frequencies. 20 However, it remains to be determined what specific subsets of cells express WT1 in normal hematopoietic cells and leukemia cells.…”

Section: Introductionmentioning

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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Very low frequencies of human normal CD34⁺ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells

Abstract: Summary. The Wilms' tumour gene, WT1, is expressed at high levels in leukaemia cells and plays an important role in leukaemogenesis. WT1 is also expressed in human normal CD34 + bone marrow (BM) cells at about 100 times lower levels than in leukaemia cells.

Cited by 101 publications

References 51 publications

GATA-1 and GATA-2 binding to 3′ enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines

GATA-1 and GATA-2 binding to 3′ enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines

Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring

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

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Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells

Abstract: Summary. The Wilms' tumour gene, WT1, is expressed at high levels in leukaemia cells and plays an important role in leukaemogenesis. WT1 is also expressed in human normal CD34 + bone marrow (BM) cells at about 100 times lower levels than in leukaemia cells.

Cited by 101 publications

References 51 publications

GATA-1 and GATA-2 binding to 3′ enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines

GATA-1 and GATA-2 binding to 3′ enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines

Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring

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

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Very low frequencies of human normal CD34⁺ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells