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The Clinical Significance of WT1 Gene Expression and WT1 Gene Mutation in Acute Myeloid Leukemia of Children

Author: WangYing
Tutor: HuShaoYan
School: Suzhou University
Course: Pediatrics
Keywords: Acute myeloid leukemia WT1 WT1 isoforms Gene mutation Single nucleotide polymorphisms
CLC: R733.71
Type: Master's thesis
Year: 2011
Downloads: 21
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Abstract


一、The significance of WT1 and WT1 gene isoforms expression in childhood acute myeloid leukemiasObjective:To explore the expression of Wilms’tumor gene 1(WT1gene) and WT1 (+17 AA) isoform in bone marrow cells of children with acute myeloid leukemia (AML) and its potential significance.Methods:Real-time quantitative reverse transcription polymerase chain reaction method (RQ-RT-PCR) was used for detecting WT1 gene and WT1 (+17 AA) isoform mRNA expression in bone marrow cells of 112 cases/times in children at different stages with acute myeloid leukemia (AML), the ratio of WT1 (+17 AA)/WT1 was calculated as well. The results were compared with those of thirty non-leukemic children in control group .Results:Expression levels of WT1 gene and WT1 (+17AA) isoform in initial acute myeloid leukemia children were significantly higher than those in the complete remission (CR) group and the control group (P<0.05); the expression levels of WT1 gene and WT1 (+17AA) isoform in relapsed group come near the levels of newly diagnosed group and resistant group, no significant difference was found among the three groups. The ratio of WT1 (+17AA)/WT1 in CR group was significantly lower than those in the newly diagnosed group, relapsed group and resistant chemotherapy group (P<0.05). The dynamic expression of WT1 gene in three cases of initial acute myeloid leukemia children indicated that the expression level of WT1 gene, WT1 (+17AA) and the ratio of WT1 (+17AA) /WT1 kept high expression or elevated again after a transient decrease in both primary resistant group and relapsed group.Conclusion:Dynamic changes of WT1 gene and WT1 (+17 AA) isoform can be used as a biomarker for evaluating prognosis and clinical efficiency in AML. 二、WT1 mutation at exon 7 in pediatric AML.Objective:To explore the rate of WT1 gene mutation at exon 7 and its potential mechanism on prognosis of pediatric AML.Methods: PCR-DNA sequencing technology was employed to detect exon 7 of WT1 gene in 47 cases of AML children in blast cells coming from the peripheral blood or bone marrow and mutation was analyzed. Homologous modeling and Optimization of Molecular Dynamics were performed to mimic WT1 spatial configuration with frame shift mutation of exon 7.Results:In 47 cases of patients with AML, 19 cases had a mutation in encoding the 434st amino acid in the second base (A→G, G/A) which is a synonymous mutation (R434R, R for Arginine). Mutation rate was 40.4%(19/47) and regarded as a single nucleotide polymorphism (SNP) after comparing with SNP database of NCBI, which had no influence on prognosis of AML. There are 3 cases with frame shift mutation in 47 cases of AML with the rate of 6.3% (3/47). The details showed as following:(1) The c.[ 1319delG] was detected in a girl with AML derived from myelodysplastic syndrome(MDS) which causes frame shift mutation. The mutation has been reported before.In this patient exon 7 in spatial configuration changed much after analyzing with Homologous modeling and Optimization of Molecular Dynamics.(2) In two cases with primary resistance to chemotherapy, one case has a mutation in c.[1342delA; 1349-1350insA; 1353delG; 1355-1356insG; 1392delA; 1400-1401insT;1405delT];c.[1415-1416insC];c.[1431delG];c.[1433-1434insA];another in c.[1345delT;1349-1350insA; 1353delG; 1355-1356insG; 1392delA], which didn’t affect the spatial configuration of exon 7 much. To our knowledge, they are first reported by our group.Conclusion:(1)WT1 mutation was detected in pediatric AML and had some relation with AML prognosis.(2)The synonymous mutation(c. 1303 A>G) didn’t contribute to the prognosis. However, mutation in frame shift may play a role in MDS transformed to AML or primary resistance to chemotherapy in AML.(3)Frame shift mutation in WT1 exon 7 may influence cells’biological nature via affecting WT1 protein interacting with other proteins or itself.

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CLC: > Medicine, health > Oncology > Hematopoietic and lymphoid neoplasms > Leukemia > Acute leukemia
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