) The Werner syndrome (WS) is an autosomal recessive disorder caused by mutations at a locus (WRN) coding for a member of the RecQ family of helicases. Patients suffer from a wide variety of benign and malignant neoplasms, with a relative high load of mesenchymal tumors. WS somatic cells exhibit mutator phenotypes and elongated S phases. The applicants are generating two mouse models of WS via targeted mutagenesis, an exon 2 knockout and an exon 26 deletion, the latter emulating the commonest variety of mutation in the Japanese population. In the proposal, in addition to the characterization of genomic instability and the determination of the prevalence and spectra of various neoplasms in homozygous deficient and wild-type mice (all on a C57BL/6 background), they will carry out comparable experiments with heterozygotic carriers, which are of special public health interest, given their relative high prevalence. Treatments with genotoxic agents, 4-nitroquinoline-1 oxide (4NQO), camptothecin, and benzo[a]pyrene, will be used as models of gene-environmental interactions with these three genotypes. In future experiments, homozygotes and heterozygotes will be crossed with other transgenic mouse lines relevant to the modulation of WRN gene action.
| Orozco, Javier I J; Knijnenburg, Theo A; Manughian-Peter, Ayla O et al. (2018) Epigenetic profiling for the molecular classification of metastatic brain tumors. Nat Commun 9:4627 |
| Schmitt, Michael W; Pritchard, Justin R; Leighow, Scott M et al. (2018) Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias. Clin Cancer Res 24:5321-5334 |
| Mikheev, Andrei M; Mikheeva, Svetlana A; Severs, Liza J et al. (2018) Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma. Mol Oncol 12:1188-1202 |
| Lee, Su-In; Celik, Safiye; Logsdon, Benjamin A et al. (2018) A machine learning approach to integrate big data for precision medicine in acute myeloid leukemia. Nat Commun 9:42 |
| Salk, Jesse J; Schmitt, Michael W; Loeb, Lawrence A (2018) Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat Rev Genet 19:269-285 |
| Davis, Luther; Zhang, Yinbo; Maizels, Nancy (2018) Assaying Repair at DNA Nicks. Methods Enzymol 601:71-89 |
| Yu, Ming; Heinzerling, Tai J; Grady, William M (2018) DNA Methylation Analysis Using Droplet Digital PCR. Methods Mol Biol 1768:363-383 |
| Knijnenburg, Theo A; Wang, Linghua; Zimmermann, Michael T et al. (2018) Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 23:239-254.e6 |
| Poston, Jacqueline N; Becker, Pamela S (2017) Controversies Regarding Use of Myeloid Growth Factors in Leukemia. J Natl Compr Canc Netw 15:1551-1557 |
| Kamath-Loeb, Ashwini S; Zavala-van Rankin, Diego G; Flores-Morales, Jeny et al. (2017) Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype. Sci Rep 7:44081 |
Showing the most recent 10 out of 137 publications
