The clinical relevance of Wilms Tumour 1 (WT1) gene mutations in acute leukaemia

Abstract

Recurrent genetic aberrations are important predictors of outcome in acute myeloid leukaemia (AML). Numerous novel molecular abnormalities have been identified and investigated in recent years adding to the risk stratification and prognostication of conventional karyotyping. Mutations in the Wilms Tumour 1 (WT1) gene were first described more than a decade ago but their clinical significance has only recently been evaluated. WT1 mutations occur in approximately 10% of adult AML patients at diagnosis and are most frequent in the cytogenetically normal (CN) AML subgroup. These mutations appear to confer a negative prognostic outcome by increasing the risk of relapse and death. Mutation frequency is higher in pediatric patients and also appears to confer a negative impact on relapse and survival. Herein, we discuss the importance of WT1 mutations in AML.

WT1 regulates murine hematopoiesis via maintenance of VEGF isoform ratio

“…Furthermore, high levels of VEGF-121 (the human equivalent of murine Vegf-a 120 ) have recently been identified as an independent prognostic factor associated with poor survival in AML. 18 Given that WT1 mutation also correlates with poor prognosis in AML, [2][3][4] and the effect of Wt1 loss of function can be abrogated by exogenous Vegf-a 164 , the WT1-VEGF pathway we describe potentially represents a novel therapeutic target in poor prognosis AML. For personal use only.…”

“…[2][3][4] Wt1 knockout mice display multiple developmental defects, including complete kidney agenesis, and die in utero, typically between embryonic days 12.5 and 13.5. 5 Transplantation of hematopoietic cells from the fetal liver and aortagonads-mesonephros region indicates that murine hematopoietic progenitor cells lacking Wt1 can engraft irradiated recipients.…”

Molecular Markers for Risk Stratification in Adult Acute Myeloid Leukemia with Normal Cytogenetics

“…Mutations in WT1 gene were found in approximately 10% of AML patients (Hou et al, 2010;Gaidzik et al, 2009;Owen et al, 2010;Paschka et al, 2008;Virappane et al 2008). Mutations are mainly localized in zinc-finger domains in exons 7 and 9 but can be also found in exons 1,2,3, and 8.…”

“…Frameshift mutations in exon 9 are less frequent but there are also missense mutations. WT1 mutations have been reported as an adverse prognostic factor in adult CN-AML and independently predict for poor outcome (Hou et al, 2010;Gaidzik et al, 2009;Owen et al, 2010;Paschka et al, 2008;Renneville et al, 2009;Virappane et al 2008). WT1 mutations lead to inferior rate of complete remission, higher incidence of relapse abd to shorter relapse-free survival and overall survival.…”

HtrA2, taming the oncogenic activities of WT1

“…61 It remains to be seen whether the nuclear HtrA2 pool can be inactivated by Akt and whether this HtrA2 phosphorylation event is primarily responsible diagnosis, cluster mainly to exons 7 and 9, and are associated with a higher rate of chemo-resistant leukemia, conferring to a negative prognostic outcome. 64 It will be important to analyse the functional properties of the mutated WT1 proteins in cancer and determine if they are resistant to HtrA2-mediated proteolysis and thereby confer chemoresistance.…”