Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia

Abstract

Wilms tumor 1 (WT1) mutations have recently been identified in approximately 10% of adult acute myeloid leukemia (AML) with normal cytogenetics (CN-AML) and are associated with poor outcome. Using array-based comparative genome hybridization in pediatric CN-AML samples, we detected a WT1 deletion in one sample. The other WT1 allele was mutated. This prompted us to further investigate the role of WT1 aberrations in childhood AML. Mutations were found in 35 of 298 (12%) diagnostic pediatric AML samples. In 19 of 35 (54%) samples, more than one WT1 aberration was found: 15 samples had 2 different mutations, 2 had a homozygous mutation, and 2 had a mutation plus a WT1 deletion. WT1 mutations clustered significantly in the CN-AML subgroup (22%; P < .001) and were associated with FLT3/ITD (43 vs 17%; P < .001). WT1 mutations conferred an independent poor prognostic significance (WT1 mutated vs wild-type patients: 5-year probability of overall survival [pOS] 35% vs 66%, P = .002; probability of event-free survival 22% vs 46%, P < .001; and cumulative incidence of relapse or regression 70% vs 44%, P < .001). Patients with both a WT1 mutation and a FLT3/ITD had a dismal prognosis (5-year pOS 21%). WT1 mutations occur at a significant rate in childhood AML and are a novel independent poor prognostic marker.

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…Of these mutations, only WT1 mutations were found in MLL-rearranged AML, and these even at a low frequency. [93][94][95][96] In more than 60% of cases a molecular aberration has not been identified, which could indicate that an MLL rearrangement on its own could be sufficient to induce leukemia. However, 40% of cases do harbor a secondary aberration and therefore it is conceivable that Gilliland's hypothesis is still a valid model for at least the large subset of MLL-rearranged pediatric AML.…”

Standardization of WT1 mRNA quantitation for minimal residual disease monitoring in childhood AML and implications of WT1 gene mutations: a European multicenter study

“…[18][19][20][21][22][23][24] Hotspots for mutations were recently detected and included, among others, exon 7 of the WT1 gene. 18,19,22 As the reverse primer of our qRT-PCR approach spans exons 6 and 7, mutations in exon 7 might theoretically affect the detection of WT1 expression, if a potential mutation is located at the binding site of the primer. To address this question, we screened for mutations within exon 7 of the WT1 gene and correlated WT1 expression and mutational status.…”

“…Screening for mutations in the WT1 gene was performed in Rotterdam on DNA and cDNA from 33/61 and 28/61 AML samples, respectively, as described earlier by Hollink et al 18 …”

“…[18][19][20][21][22][23][24] As pediatric AML is a rare disease, international cooperation is necessary for monitoring substantial numbers of patients to obtain statistically powerful results. Although various methodologies have been applied in the past, a uniform approach that has been proven to ensure reproducible, accurate and comparable results on a multicenter basis is currently unavailable.…”

High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome

“…21 NPM1, CEBPA, WT1, NRAS, KRAS, PTPN11, CKIT and FLT3 hotspot mutational screening was performed as previously described. [22][23][24][25][26] Overexpression of EVI1 was previously established by gene expression profiling and real-time quantitative (RQ)-PCR. 27 Microarray-based gene expression profiling Integrity of total RNA was checked using the Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA).…”