Measurable residual disease monitoring using Wilms tumor gene 1 expression in childhood acute myeloid leukemia based on child‐specific reference values

Abstract

Background Measurable/minimal residual disease (MRD) monitoring can predict imminent hematological relapse in acute myeloid leukemia (AML). The majority of childhood AML patients do not harbor fusion genes or mutations applicable as MRD markers and overexpression of Wilms tumor gene 1 (WT1) may constitute a useful monitoring target. However, age‐specific reference values in healthy hematopoiesis and standardization of WT1 assessment are prerequisites for clinical utility. Procedure We investigated WT1 expression across age in hematologically healthy controls (n = 109), during suspected infection (n = 90) and bone marrow (BM) regeneration (n = 13). WT1 expression in AML at diagnosis (n = 91) and during follow‐up (n = 30) was compared with age‐specific reference values. Results WT1 expression correlated with age and showed higher levels in both BM and peripheral blood (PB) in children compared with adults (P < 0.001 and P = 0.01). WT1 expression from healthy hematopoiesis was lower in PB compared with BM (WT1BM/WT1PB = 8.6, 95% CI: 5.3–13.7) and not influenced by infection nor BM regeneration. At AML diagnosis, 66% had more than 20‐fold WT1 overexpression in PB or BM (PB 74%; BM 45%). WT1 was quantified in 279 PB samples during follow‐up. All 11 patients with PB sampling within 4 months of disease recurrence displayed WT1 overexpression by a median of 1.9 months (range, 0.7–9.7) before hematological relapse. Conclusions This study defines child‐specific reference values for WT1 expression in healthy hematopoiesis and demonstrates that WT1 expression in PB is a useful post‐treatment monitoring tool in childhood AML. Based on these observations, we propose definitions for childhood AML molecular relapse using WT1 overexpression.

Integration of measurable residual disease by WT1 gene expression and flow cytometry identifies pediatric patients with high risk of relapse in acute myeloid leukemia

“…The incidence of WT1 gene overexpression in pediatric AML, as reported in previous studies, ranges from 76% to 83% (9, 15-17), which aligns with the current results. However, Juul-Dal et al showed a much lower incidence of WT1 overexpression (45%) (1). Previous pediatric studies showed that WT1 gene overexpression was significantly associated with M4 FAB subtype, this goes in agreement with our results (91.4% of M4 cases had high WT1 levels, p=0.018) (9,18,19).…”

“…Previous pediatric studies showed that WT1 gene overexpression was significantly associated with M4 FAB subtype, this goes in agreement with our results (91.4% of M4 cases had high WT1 levels, p=0.018) ( 9 , 18 , 19 ). A high incidence of WT1 overexpression in CBF AML was reported, ranging from 87% up to 100% (p<0.001), while a strong inverse correlation with the presence of KMT2A gene rearrangement (p<0.001) suggesting downregulation of WT1 activating pathway in this leukemia subset, as demonstrated in the present study ( 1 , 9 , 20 ).…”

“…However, Juul-Dal et al. showed a much lower incidence of WT1 overexpression (45%) ( 1 ). Previous pediatric studies showed that WT1 gene overexpression was significantly associated with M4 FAB subtype, this goes in agreement with our results (91.4% of M4 cases had high WT1 levels, p=0.018) ( 9 , 18 , 19 ).…”

“…The survival rate of pediatric patients with acute myeloid leukemia (AML) approached 70%, with approximately 30% experiencing relapse, which is the main cause of treatment failure ( 1 ). Measurable residual disease (MRD) is an important biomarker in AML patients used for prognosis and response assessments ( 2 ).…”

State-Transition Analysis of Time-Sequential Gene Expression Identifies Critical Points That Predict Leukemia Development

“…Overexpression of WT1 has been found to predict poor prognosis and minimal residual disease in AML(Adnan-Awad et al, Becker et al, 2010;Løvvik Juul-Dam et al, 2019). Prkd1 encodes a serine/threonine protein kinase and is part of all top 3 ranked GO terms enriched for persistent events.…”