Here, the research team described the hematologic phenotype of a knock-in mouse model of a Wt1 mutation, described in cases of human leukemia. They crossbred Wt1+/R394W mice with knock-in Flt3+/ITD mice, and show that mice with both mutations develop a transplantable MDS/MPN, with more aggressive features compared to either single mutant mouse model.
Dr. Patrick Brown from the Sidney Kimmel Comprehensive Cancer Center & the Department of Pediatrics, at Johns Hopkins University School of Medicine, in Baltimore, MD, USA and Dr. Colleen E. Annesley from the Department of Pediatrics, at the University of Washington, in Seattle, WA, USA said, "The Wilms tumor 1 gene encodes a zinc finger transcriptional regulator that acts as a tumor suppressor in various cell types, with target genes implicated in cell differentiation, apoptosis and cell cycle regulation."
"The Wilms tumor 1 gene encodes a zinc finger transcriptional regulator that acts as a tumor suppressor in various cell types, with target genes implicated in cell differentiation, apoptosis and cell cycle regulation."
- Dr. Patrick Brown, Sidney Kimmel Comprehensive Cancer Center & the Department of Pediatrics, at Johns Hopkins University School of Medicine and Dr. Colleen E. Annesley, Department of Pediatrics, at the University of Washington
The first evidence that a WT1 mutation could be leukemogenic was a report describing a Wilms tumor survivor with WAGR syndrome, who by definition harbored a germline heterozygous deletion of the WT1 gene, and later developed acute myeloid leukemia with a new somatic WT1 mutation in the remaining allele.
Mutations in exon 7 tend to be frameshift mutations and often occur as biallelic compound heterozygous mutations, resulting in a truncated WT1 protein and loss of the zinc finger DNA-binding domain. Recent studies of large MDS cohorts have defined WT1 mutations as an independent poor prognostic indicator, and have shown correlations of WT1 mutations with lower hemoglobin levels and a higher percentage of bone marrow blasts.
Even when accounting for the poor prognostic implication of FLT3/ITD mutations, WT1 mutations have been independently associated with treatment failure and a poor prognosis. To specifically investigate the relationship between WT1 mutations and FLT3/ITD mutations in human AML, we created a novel mouse model by cross-breeding mice with a constitutively knocked-in Flt3/ITD mutation with Wt1+/R394W mice.
The Patrick Brown/Colleen E. Annesley research team concluded, "we demonstrate here that the presence of Wt1+/R394W in the murine hematopoietic system leads to the development of MDS with single lineage dysplasia, manifested as anemia and erythroid dysplasia, and contributing to a trend in decreased survival."
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DOI - https://doi.org/10.18632/oncotarget.26238
Full text - https://www.oncotarget.com/article/26238/text/
Correspondence to - Patrick Brown - pbrown2@jhmi.edu and Colleen E. Annesley - colleen.annesley@seattlechildrens.org
Keywords - WT1, Wilms tumor 1, myelodysplastic syndrome, AML, FLT3
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