Table of Contents
1
UI - 11601276
AU - Mi Y; Wang L; Bian S; Meng Q; Chen G; Wang J
TI -
Effect of WT1 gene expression on cell growth and proliferation in
myeloid leukemia cell lines.
SO - Chin Med J (Engl) 1999 Aug;112(8):705-8
AD - Institute of Hematology and Blood Diseases Hospital, CAMS, PUMC, Tianjin
300020, China.
OBJECTIVE: To investigate the effects and mechanism of Wilms' tumor
(WT1) antisense oligonucleotides (AS-oligomers) on proliferation and
apoptosis in myeloid leukemia cell lines. METHODS: K562 and HL-60 cells
were cultured in presence of WT1 oligomers. Both cell lines express WT1
gene with no p53 protein expression. Cells growth, apoptosis and
expression of WT1, bcl-2 genes were analysed using
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylmetrazolium bromide (MTT)
colorimetric assay, flow cytometry and reverse transcription-polymerase
chain reaction (RT-PCR) methods. RESULTS: WT1 antisense oligonucleotides
inhibited cellular proliferation of K562 cells and the effect was
concentration-dependent. When cultured at concentration of 200
micrograms/ml oligomers, growth inhibition was 46.2% for antisense
oligonucleotide cultivated group and 28.1% for sense oligonucleotide
cultured group (P = 0.008) respectively. WT1 antisense oligonucleotide
can induce apoptosis of K562 and HL-60 cells. Percentages of apoptotic
cells in antisense oligonucleotide and sense oligonucleotide treated
groups were 30.88% versus 13.62% for K562 cells and 40.15% versus 4.23%
for HL-60 cells. However the growth of HL-60 cells and expression of
bcl-2 gene were unaffected. CONCLUSIONS: The WT1 gene is related with
proliferation and apoptosis of leukemic cells. Effect of anti-apoptosis
may be independent of the cellular p53 status and bcl-2 expression. WT1
gene may play an important role in leukemogenesis.
2
UI - 11601201
AU - Guo X; Xu S; Dong Z
TI -
[WT1 gene expression in leukemia patients and its correlation with
prognosis and multidrug resistance]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Feb;20(2):69-72
AD - Department of Hematology, Second Hospital, Hebei Medical University,
Shijiazhuang 050000.
OBJECTIVE: To evaluate the value of expression of WT1 gene in predicting
the prognosis of leukemia patients, and explore the relationship between
WT1 gene expression and multidrug resistance and cell apoptosis.
METHODS: Expressions of WT1, MRP and mdr1 were measured in 68 leukemia
patients by RT-PCR method. Expression of bcl-2 was measured in 32 AML
patients by immunofluorescence flow cytometry. RESULTS: Expression of
WT1 was revealed in 36 of 68 leukemia patients and none of 23 normal
controls. Complete remission rate (59.46%) was lower in WT1 positive
patients than that (87.10%, P = 0.011) in WT1 negative patients. The
rate of MRP expression was also higher in patients with WT1 expression
(58.33%), than in those without WT1 expression (32.26%, P = 0.033).
Thirty-two AML patients were divided into high-, intermediate-, and
low-risk groups according to the expression of WT1 and bcl-2. CR rates
were significantly different among these 3 groups (33.33% for high-,
47.37% for intermediate-, and 100% for low-risk group, P < 0.05).
CONCLUSION: The expression of WT1 can predict the treatment outcome and
the prognosis for leukemia patients. Expression of WT1 is the most
important risk factor, and the coexpression of WT1 and bcl-2 predicts
poor prognosis of AML patients.
3
UI - 11721364
AU - Wu X; Wang Y; Pei X
TI -
[Effect of WT1 antisense oligonucleotide on proliferation and apoptosis
of human leukemia cells]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Dec;20(12):631-3
AD - General Hospital of PLA, Beijing 100853.
OBJECTIVE: To elucidate the effect of WT1 antisense oligonucleotide on
and the role of WT1 gene in proliferation and apoptosis of leukemia
cells. METHODS: K562, U937, HL-60 cell lines, leukemic blast from 8
acute myeloid leukemia patients and normal bone marrow cells from 8
healthy subjects were treated in vitro with WT1 antisense
oligonucleotide (WT1 ASO) targeting to the translation site of WT1 mRNA.
The inhibitory effect on growth of leukemia cells was measured by Trypan
blue exclusion and colony-forming unit assay. Apoptosis was measured by
flow cytometric analysis and DNA fragmentation assay. RESULTS: WT1 ASO
significantly inhibited the proliferation of K562 cells expressing WT1
and leukemic blast of 4 in 8 acute myeloid leukemia patients, but didn't
inhibit the growth of U937 cells which had no WT1 expression and CFU-GM
of normal marrow cells from 8 healthy subjects. Whereas WT1 sense
oligonucleotide (WT1 SO) had no effect on the proliferation of K562
cells, U937 cells and the CFU-GM of normal marrow cells. WT1 ASO could
induce apoptosis of K562 cells and the level of apoptosis was increased
markedly when combined with Vp16; WT1 ASO alone couldn't induce
apoptosis of HL-60 cells, but could increase the apoptosis when combined
with Vp16. CONCLUSION: WT1 ASO specifically inhibit the growth of
leukemic cells, induce apoptosis of K562 cells and increase the
apoptosis susceptibility of leukemia cells to Vp16. WT1 plays an
important role in proliferation and apoptosis of leukemic cells.
4
UI - 11717330
AU - Ravenel JD; Broman KW; Perlman EJ; Niemitz EL; Jayawardena TM; Bell DW;
TI -
Haber DA; Uejima H; Feinberg AP
Loss of imprinting of insulin-like growth factor-II (IGF2) gene in
distinguishing specific biologic subtypes of Wilms tumor.
SO - J Natl Cancer Inst 2001 Nov 21;93(22):1698-703
AD - Institute of Genetic Medicine, The Johns Hopkins University School of
Medicine, Baltimore, MD 21205, USA.
BACKGROUND: Loss of imprinting (LOI) of the insulin-like growth
factor-II (IGF2) gene, an epigenetic alteration associated with
expression of the normally silent maternal allele, was observed first in
Wilms tumor. Although LOI has subsequently been detected in most adult
tumors, the biologic role of LOI in cancer remains obscure. We analyzed
the imprinting status of Wilms tumors with respect to pathologic
subtype, stage, and patient's age at diagnosis and examined the
expression of genes potentially affected by LOI. METHODS: Of 60 Wilms
tumors examined, 25 were informative for an ApaI polymorphism in the
IGF2 gene, allowing analysis of allele-specific gene expression, and
could be classified by pathologic subtype. Gene expression was measured
quantitatively by real-time polymerase chain reaction, and pathologic
analysis was blinded for genetic status. All statistical tests were
two-sided. RESULTS: We observed LOI of IGF2 in nine (90%) of 10 Wilms
tumors classified as having a pathologic subtype associated with a later
stage of renal development and in only one (6.7%) of 15 Wilms tumors
with a pathologic subtype associated with an earlier stage of renal
development (P< .001). LOI was associated with a 2.2-fold increase (95%
confidence interval [CI] = 1.6-fold to 3.1-fold) in IGF2 expression (P<
.001). Children whose Wilms tumors displayed LOI of IGF2 were
statistically significantly older at diagnosis (median = 65 months;
interquartile range [IQR] = 47-83 months) than children whose tumors
displayed normal imprinting (median = 24 months; IQR = 13-35 months; P<
.001). CONCLUSIONS: These data demonstrate a clear relationship between
LOI and altered expression of IGF2 in Wilms tumors and provide a
molecular basis for understanding the divergent pathogenesis of this
cancer. Analysis of LOI could provide a valuable molecular tool for the
classification of Wilms tumor.
5
UI - 11739471
AU - Makrigiannakis A; Coukos G; Mantani A; Prokopakis P; Trew G; Margara R;
TI -
Winston R; White J
Expression of Wilms' tumor suppressor gene (WT1) in human endometrium:
regulation through decidual differentiation.
SO - J Clin Endocrinol Metab 2001 Dec;86(12):5964-72
AD - Department of Reproductive Science and Medicine, Imperial College School
of Medicine, Hammersmith Hospital, W12 ONN OHS, London, United Kingdom.
makrigia@med.uoc.gr
The Wilms' tumor suppressor gene (WT1) encodes a zinc-finger containing
transcription factor that is selectively expressed in the developing
urogenital tract and functions as a tissue-specific developmental
regulator. In addition to its gene-regulatory function through DNA
binding properties, WT-1 also regulates transcription by formation of
protein-protein complexes. These properties place WT-1 as a major
regulator of cell growth and differentiation. In view of these
observations, we studied WT1 mRNA and protein in human endometrial
extracts and in endometrial stromal cells (ESCs) differentiating into
decidual cells in vitro, by RT-PCR and Western blotting, respectively.
WT1 protein expression was also studied in situ in the proliferative and
the secretory phase of the menstrual cycle in the early pregnant state.
Analysis by PCR of total RNA prepared from human ESCs demonstrated the
presence of WT1 mRNA and four WT1 mRNA splice variants. Western blot
analysis of nuclear protein extracts from ESCs yielded one
immunoreactive protein of the expected size (approximately 52-54 kDa)
recognized by the WT1 antibody. Immunohistochemical staining showed that
WT1 protein is localized only to nuclei of human endometrial stromal
cells. It remains constant in the proliferative and the secretory phase
of the menstrual cycle and is increased remarkably during
decidualization in early pregnancy. ESCs decidualized in vitro were
investigated for WT-1 expression, which confirmed that decidualizing
stimuli (E2, medroxy-progesterone-acetate, and relaxin for 12 d or cAMP
and progesterone for 1-4 d) induced WT-1 mRNA (P < 0.05) and increased
protein levels (P < 0.05). These data indicate that in humans the WT1
gene is expressed in ESCs and its mRNA and protein levels remain
constant in the proliferative and the secretory phase of the menstrual
cycle and that WT1 mRNA and protein expression increases significantly
in ESCs when these cells differentiate into decidual cells.
6
UI - 1769647
AU - Mannens M; Hoovers JM; Bleeker-Wagemakers EM; Redeker E; Bliek J;
TI -
Overbeeke-Melkert M; Saunders G; Williams B; van Heyningen V; Junien C;
et al
The distal region of 11p13 and associated genetic diseases.
SO - Genomics 1991 Oct;11(2):284-93
AD - Institute of Human Genetics, University of Amsterdam, The Netherlands.
The distal region of human chromosome band 11p13 is believed to contain
a cluster of genes involved in the development of the eye, kidney,
urogenital tract, and possibly the nervous system. Genetic abnormalities
of this region can lead to Wilms tumor, aniridia, urogenital
abnormalities, and mental retardation (WAGR syndrome). Using 11 DNA
markers covering the entire distal region of 11p13, including the WAGR
region, we have carried out molecular studies on 58 patients with one or
more features of this syndrome and patients with other diseases or
structural cytogenetic abnormalities associated with 11p13. Cytogenetic
analyses were performed in all cases. In 12 patients we were able to
demonstrate deletions of this region. In 2 patients balanced
translocations and in 2 additional patients duplications of this region
were characterized. In total, 5 chromosomal breakpoints within 11p13
were identified. One of these breakpoints maps within the smallest
region of overlap of WAGR deletions. Moreover, we were unable to
demonstrate constitutional deletions in a candidate sequence for the
Wilms tumor gene or any other marker in 2 patients with aniridia and
urogenital abnormalities, 4 patients with Wilms tumor and urogenital
abnormalities, 5 patients with bilateral Wilms tumors, and 3 familial
Wilms tumor cases. We suggest that the molecular techniques used here
(heterozygosity testing for polymorphic markers mapping between AN2 and
WT1 and deletion analysis by dosage, cytogenetic analysis, or in situ
hybridization) can be employed to identify sporadic aniridia patients
with and without increased tumor risk.
7
UI - 2562179
AU - Hastie ND; Bickmore W; Pritchard-Jones K; Porteous DJ; van Heyningen V
TI -
Wilms tumour: a developmental anomaly.
SO - Princess Takamatsu Symp 1989;20():145-50
AD - MRC Human Genetics Unit, Western General Hospital, Edinburgh, U.K.
Wilms tumour (WT) is a developmental anomaly of the kidney which results
from loss of function of at least one so called tumour suppressor gene
on chromosome 11. The position of the gene at chromosome 11p13 is known
through the association of WT with aniridia (lack of an iris), mental
retardation and genitourinary abnormalities in the WAGR syndrome. Here
we discuss the high resolution mapping studies to locate the position of
the gene and conclude that the gonadal abnormalities in WAGR patients
may be due to a defect in the WT gene itself. In support of this role in
genitourinary development we show that a candidate WT gene is expressed
in specific regions of the developing kidney and in fetal and embryonic
gonads.
8
UI - 7593321
AU - Bickmore WA; Carothers AD
TI -
Factors affecting the timing and imprinting of replication on a
mammalian chromosome.
SO - J Cell Sci 1995 Aug;108 ( Pt 8)():2801-9
AD - MRC Human Genetics Unit, Western General Hospital, Edinburgh, Scotland,
UK.
Fluorescence in situ hybridisation has been used to follow replication
of the short arm of human chromosome 11 using chromosome anomalies to
distinguish the maternally-and paternally-derived homologues. The
temporal difference in replication timing within and between chromosomes
has been estimated by combining S phase detection with dual colour
fluorescence in situ hybridisation. Proximal regions of 11p, including
the WT1 gene, tend to replicate earlier on the maternally-derived
chromosome than on the paternally-derived homologue. More distal parts
of 11p (including the IGF2 gene) have the opposite imprint. The average
difference in replication timing between homologous loci in the
population of cells is small compared to the differences between loci
along a single chromosome. The imprint is not strictly adhered to since
many nuclei have hybridisation patterns opposite to the trend within the
population. The nature of the imprinting signal has been investigated.
Absolute replication time, but not the imprint, was affected by
azacytidine, an inhibitor of DNA methylation. The replication imprint
was modified by treatments that inhibit histone deacetylation. We
suggest that replication imprinting reflects differences in chromatin
structure between homologues.
9
UI - 10921316
AU - Hata J; Fukuzawa R; Takata A; Kikuchi H
TI -
[Wilms' tumors and malformation complexes]
SO - Nippon Rinsho 2000 Jul;58(7):1419-25
AD - Department of Pathology, Keio University School of Medicine.
Wilms' tumor is an embryonal tumor which is derived from metanephric
metanephric blastema. The occurrence of both sporadic and hereditary
forms, along with various congenital abnormalities of Wilms' tumor
suggest that the tumors develop when a predisposing germ line mutation
is accompanied by a second mutation. The existence of both gross
chromosomal abnormalities has led to the genetic characterization of a
number of loci involved in the development of Wilms' tumor. A tumor
suppressor gene for Wilms' tumor, WT1, has been isolated from the 11p13
region. The product of this gene is a transcription factor with four
zinc fingers. Because of expression of WT1 is limited to the developing
glomeruli of the kidneys and the genital ridge, it is thought to have a
functional role in renal and gonadal organogesis. Thus dysfunction of
WT1 causes loss of normal regulation of proliferation and leads to tumor
formation and occurrence of Wilms' tumor anomaly complexes. The role of
the imprinting genes, H19 and IGF2 in oncogenesis of Wilms' tumors are
also discussed.
10
UI - 11518820
AU - Sakamoto J; Takata A; Fukuzawa R; Kikuchi H; Sugiyama M; Kanamori Y;
TI -
Hashizume K; Hata JI
A novel WT1 gene mutation associated with wilms' tumor and congenital
male genitourinary malformation.
SO - Pediatr Res 2001 Sep;50(3):337-44
AD - Department of Pediatric Surgery, University of Tokyo Faculty of
Medicine, Tokyo, Japan.
WT1 is located on the short arm of human chromosome 11 and consists of
10 coding exons. Mutations of this gene have been reported to be the
cause of Wilms' tumor, congenital male genitourinary malformations,
and/or renal disorders. We describe here a novel WT1 gene mutation, i.e.
a point mutation at intron 7 (+2) in both the tumor and the germline
cells of a patient with Wilms' tumor and congenital male genitourinary
malformation, but without renal disorder. The position of the mutation
is at a splice donor site of intron 7, which causes the splicing out of
exon 7 and generates a truncated protein. This type of mutation in the
WT1 zinc finger domain has not been reported before. The mutation is of
paternal origin and is heterozygous in the germline cells. In the tumor
cells, however, the maternal allele is largely lost, from 11p12 to
11p15, which results in maternal loss of heterozygosity. These results,
together with the data from previous reports, suggest that WT1 may
function in gonadogenesis, nephrogenesis, and Wilms' tumor
tumorigenesis.
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