title: Homology modeling and molecular dynamics studies of Wilms' tumor gene 1 frameshift mutations in exon 7.
abstract: As a transcription factor, the Wilms' tumor 1 (WT1) gene plays an important role in leukemogenesis. The impact of WT1 gene mutations has been reported in acute myeloid leukemia (AML). However, the number of available studies on the spatial configuration changes following WT1 mutation is limited. In this study, we sequenced the mutation in exon 7 of the WT1 gene in 60 children with newly diagnosed AML and the spatial configuration of WT1 with frameshift mutations in exon 7 was evaluated using the software for homology modeling and optimization of molecular dynamics. Three cases with frameshift mutations in exon 7 were identified (3/60; mutation rate, 5%). One case had a mutation that had been previously described, whereas the remaining two mutations were first described in our study. Of the three cases, one case presented with antecedent myelodysplastic syndrome (MDS) and the remaining two cases exhibited primary resistance to induction chemotherapy. The spatial configuration analysis demonstrated that the three mutations affected the spatial structure of exon 7 and even affected exon 8 compared to its wild-type. This study demonstrated that the frameshift mutation in exon 7 of the WT1 gene is a poor prognostic factor for children with AML, partly through the spatial configuration changes following frameshift mutations of WT1, which highlights the structure-based function analysis and may facilitate the elucidation of the pathogenesis underlying WT1 gene mutations.
authors.affiliation: Department of Hematology and Oncology, The Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China.
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Hematology and Oncology, The Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hematology and Oncology, The Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China.
authors.forename: Shuiyan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Hematology and Oncology, The Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China.
authors.forename: Mingying
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Oncology, The Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Pan
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Shen
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Qi
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Jiannong
authors.initials: J
authors.lastname: Cen
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Zixing
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Center for Systems Biology, Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Bairong
authors.initials: B
authors.lastname: Shen
authors.affiliation: Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Chen
keywords: Wilms' tumor gene 1; acute myeloid leukemia; children; frameshift mutation; myelodysplastic syndrome; resistance to chemotherapy