Knock-in of the Wt1 R394W mutation causes MDS and cooperates with Flt3/ITD to drive aggressive myeloid neoplasms in mice
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Colleen E. Annesley1, Cara Rabik2,3, Amy S. Duffield2,4, Rachel E. Rau5, Daniel Magoon2, Li Li2, Vicki Huff6, Donald Small2,3, David M. Loeb7 and Patrick Brown2,3
1Department of Pediatrics, University of Washington, Seattle, WA, USA
2The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
4Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
5Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
6Department of Molecular Genetics/Cancer Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
7Current affiliation: Departments of Pediatrics and Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
Patrick Brown, email: email@example.com
Colleen E. Annesley, email: firstname.lastname@example.org
Keywords: WT1; Wilms tumor 1; myelodysplastic syndrome; AML; FLT3
Received: August 28, 2018 Accepted: September 05, 2018 Published: October 19, 2018
Wilms tumor 1 (WT1) is a zinc finger transcriptional regulator, and has been implicated as both a tumor suppressor and oncogene in various malignancies. Mutations in the DNA-binding domain of the WT1 gene are described in 10–15% of normal-karyotype AML (NK-AML) in pediatric and adult patients. Similar WT1 mutations have been reported in adult patients with myelodysplastic syndrome (MDS). WT1 mutations have been independently associated with treatment failure and poor prognosis in NK-AML. Internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase 3 (FLT3) commonly co-occur with WT1-mutant AML, suggesting a cooperative role in leukemogenesis. The functional role of WT1 mutations in hematologic malignancies appears to be complex and is not yet fully elucidated. Here, we describe the hematologic phenotype of a knock-in mouse model of a Wt1 mutation (R394W), described in cases of human leukemia. We show that Wt1+/R394W mice develop MDS which becomes 100% penetrant in a transplant model, exhibit an aberrant expansion of myeloid progenitor cells, and demonstrate enhanced self-renewal of hematopoietic progenitor cells in vitro. We crossbred Wt1+/R394W mice with knock-in Flt3+/ITD mice, and show that mice with both mutations (Flt3+/ITD/Wt1+/R394W) develop a transplantable MDS/MPN, with more aggressive features compared to either single mutant mouse model.
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