Frequency and clinical impact of WT1 mutations in the context of CEBPA-mutated acute myeloid leukemia

Several studies have confirmed that mutations in the Wilms tumor 1 (WT1) gene occur in adult acute myeloid leukemia (AML). However, few data are available regarding the incidence of WT1 mutations in CEBPA mut AML and their impact. We retrospectively analyzed the frequency and clinical impact of WT1 mutations in 220 newly diagnosed AML patients with CEBPA mutations(CEBPA mut ). Chromosome karyotype analysis was performed by R or G banding method and further confirmed either by fluorescence in situ hybridization (FISH) and/or by multiple reverse transcription polymerase chain reaction (multiple RT-PCR). Mutations were detected with a panel of 112mutational genes using next-generation sequencing (NGS). Overall, 30 WT1 mutations were detected in 29 of the 220 CEBPA mut AML patients (13.18%) screened. These mutations clustered overwhelmingly in exon 7 (n=16). WT1 mutations were found to be significantly more frequent in AML patients with double-mutated CEBPA (CEBPA dm ) than in AML patients with single-mutated CEBPA (17.36%vs. 8.08%, P = 0.043). Among WT1-mutated patients, the most common co-mutation was FLT3-ITD (n = 7, 24.14%), followed by NRAS (n = 5, 17.24%), CSF3R (n = 4, 13.79%), GATA2 (n = 4, 13.79%), and KIT (n = 4, 13.79%). The most frequent functional pathway was signaling pathways inas many as 62.07% of cases. Notably,the concomitant mutations in epigenetic regulatorswere inversely correlated with WT1 mutations(P = 0.003). CEBPA dm AML patients with WT1 mutations had inferior relapse-free survival, event-free survival and overall survival compared with patients CEBPA dm AML without WT1 mutations (P = 0.002, 0.004, and 0.010, respectively). Our data showed that WT1 mutations are frequently identified in CEBPA mut AML, especially in CEBPA dm AML. CEBPA mut AML patients with WT1 mutations show distinct spectrum of comutations. In the context of CEBPA dm AML, WT1 mutations predict a poor prognosis.