Low WT1 Expression Identifies a Subset of Acute Myeloid Leukemia with a Distinct Genotype

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Wilms' tumor gene 1 (WT1) is a biomarker for measurable residual disease (MRD) in acute myeloid leukemia (AML).
• WT1 is overexpressed in most AML cases at diagnosis, but its role in low-expression scenarios is unclear.
• This study focuses on the mutational landscape and clinical outcomes in AML patients with low WT1 expression.

Purpose of the Study:

• To investigate the mutational profile of AML patients with low WT1 expression at diagnosis.
• To analyze the clinical outcomes associated with low WT1 expression in AML.
• To compare the findings with the general AML population and identify distinct characteristics.

Main Methods:

• Analysis of 34 AML patients with low WT1 expression (WT1/ABL1 < 250) diagnosed between 2013-2017.
• Next-generation sequencing (NGS) to assess mutations in 32 common AML-related genes.
• Comparison of mutation status and clinical outcomes with the general AML cohort.

Main Results:

• Patients with low WT1 expression had a significantly higher mutational burden (median 3.4 mutations/patient).
• Clonal hematopoiesis (CHIP) or myelodysplasia-related (MR) mutations (e.g., ASXL1, TET2, SRSF2) were prevalent.
• Low WT1 expression AML showed overall survival comparable to myelodysplasia-related AML.

Conclusions:

• Low WT1 expression in AML is linked to a unique and complex mutational profile.
• Frequent CHIP and MR mutations characterize this subgroup of AML patients.
• The findings highlight a distinct genetic signature associated with low WT1 expression in AML.