Abstract
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.
Highlights
The Wilms tumor 1 gene (WT1) 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 [1, 2]
We found that Wt1+/R394W mice develop myelodysplastic syndrome (MDS), which is recapitulated with 100% penetrance in a transplant mouse model at a shortened latency
We show that mice harboring both Wt1/R394W and Flt3/Internal tandem duplication (ITD) mutations develop an aggressive MDS/myeloproliferative neoplasm (MPN) phenotype
Summary
The Wilms tumor 1 gene (WT1) 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 [1, 2]. Clusters of mutational “hot spots” occur in exons 7 and 9, which encode the zinc finger DNA-binding domain. 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 [9, 11]. Recent studies of large MDS cohorts have defined WT1 mutations as an independent poor prognostic indicator [16], and have shown correlations of WT1 mutations with lower hemoglobin levels and a higher percentage of bone marrow blasts [17]
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