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. 2025 Apr 3;17(7):1213.
doi: 10.3390/cancers17071213.

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

Michela Rondoni  1 , Giovanni Marconi  1   2 , Annalisa Nicoletti  3 , Barbara Giannini  3 , Elisa Zuffa  3 , Maria Benedetta Giannini  4 , Annamaria Mianulli  5 , Marianna Norata  4 , Federica Monaco  5 , Irene Zaccheo  4 , Serena Rocchi  1 , Beatrice Anna Zannetti  1 , Adele Santoni  6 , Claudio Graziano  3 , Monica Bocchia  6 , Francesco Lanza  1   2
Affiliations

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

Michela Rondoni et al. Cancers (Basel). .

Abstract

Background: Wilms' tumor gene 1 (WT1) is a critical player in acute myeloid leukemia (AML), often serving as a biomarker for measurable residual disease (MRD). The WT1 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. Methods: We analyzed 34 AML patients with low WT1 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. Results: 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 ASXL1, TET2, and SRSF2, were present in most patients with low WT1 expression. All but one case of NPM1- or FLT3-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. Conclusions: Low WT1 expression in AML is associated with a distinct and complex mutational profile, marked by frequent CHIP and MR mutations.

Keywords: AML; CHIP mutations; WT1; low WT1 expression; marrow dysplasia; measurable residual disease; next-generation sequencing; prognosis.

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Conflict of interest statement

M.R. was a consultant for or was included in the speakers bureau for Novartis, Gentili, Blueprint, and Jazz. G.M. received research funds from AbbVie, Astellas, AstraZeneca, Daiichi Sankyo, Pfizer, and Syros and was a consultant for or was included in the speakers bureau for AbbVie, Astellas, AstraZeneca, Immunogen, Janssen, Menarini/Stemline, Pfizer, Ryvu, Servier, Syros, and Takeda. F.L. received research funds from Pfizer and Alexion and is a consultant for Sobi, Roche, AbbVie, Amgen, and Novartis. The remaining authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Figures

Figure 1
Figure 1
(A) Incidence of gene mutations in cohort of 29 patients with low-level WT1 expression. (B) Mutation per type. (C) Median variant allele fraction for mutations in each gene.
Figure 2
Figure 2
Kaplan-Meier survival of 26 patients from our laboratory’s low-level WT1 cohort.
See this image and copyright information in PMC

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