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

<b>Background:</b> Wilms' tumor gene 1 (<i>WT1</i>) is a critical player in acute myeloid leukemia (AML), often serving as a biomarker for measurable residual disease (MRD). The <i>WT1</i> gene is overexpressed in the majority of AML cases at diagnosis, with apparently no correlation with prognosis, and in the meantime, its role in patients with low-level expression is still undefined. This study investigates the mutational landscape and clinical outcomes of AML patients with low WT1 expression at diagnosis. <b>Methods:</b> We analyzed 34 AML patients with low <i>WT1</i> expression (WT1/ABL1 < 250) diagnosed and treated from 2013 to 2017 at three institutions. Next-generation sequencing (NGS) was employed to investigate the mutational status of 32 genes commonly mutated in AML. The presence of specific mutations, as well as clinical outcomes, was compared to the general AML population. <b>Results:</b> Patients with low WT1 expression showed a significantly higher mutational burden, with a median of 3.4 mutations per patient, compared to the general AML population. Notably, clonal hematopoiesis (CHIP) or myelodysplasia-related (MR) mutations, particularly in <i>ASXL1</i>, <i>TET2</i>, and <i>SRSF2</i>, were present in most patients with low WT1 expression. All but one case of <i>NPM1</i>- or <i>FLT3</i>-mutant AML in the low-WT1 cohort harbored more CHIP or MR mutations. Patients with low WT1 expression had an overall survival (OS) that was superimposable to the OS expected in MR AML. <b>Conclusions:</b> Low WT1 expression in AML is associated with a distinct and complex mutational profile, marked by frequent CHIP and MR mutations.