Prognostic relevance of Wilms tumor 1 (WT1) gene Exon 7 mutations in-patient with cytogenetically normal acute myeloid leukemia

Hua

et al. 2021

Preprint

Introduction: 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 CEBPAmut AML and their impact. Methods: We retrospectively analyzed the frequency and clinical impact of WT1 mutations in 220 newly diagnosed AML patients with CEBPA mutations. 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 112 mutational genes using next-generation sequencing (NGS). FLT3-ITD, NPM1 and CEBPA mutation were detected by PCR Sanger sequencing.Results: Overall, 30 WT1 mutations were detected in 29 of the 220 patients (13.18%) screened. These mutations clustered overwhelmingly in exon 7 (16 mutations in 15 patients), but they were also detected in exon 8 (n=6) and exon 9 (n=8). WT1-mutated (WT1mut) patients presented with lower platelet counts (P=0.0481), higher WT1 expression (P=0.0371), and a negative trend with the M5 subtype (P=0.07) compared to WT wild-type (WTwt) patients. WT1 mutations were found to be significantly more frequent in AML patients with double-mutated CEBPA (CEBPAdm) than in AML patients with single-mutated CEBPA (P=0.043). Of note, the concomitant mutations in epigenetic regulators were inversely correlated with WT1 mutations (P=0.003). Patients with newly diagnosed WT1mut AML had inferior relapse-free survival, event-free survival and overall survival compared with patients with WT1wt AML (P=0.002, 0.004, and 0.010, respectively). Conclusion: Our data showed that WT1 mutations are frequently identified in CEBPAmut AML, especially in CEBPAdm AML. Patients with WT1 mutations show distinct clinical features, a spectrum of comutations, and poor prognosis compared to WT1 wild-type patients.

Section: Discussionmentioning

confidence: 79%

Frequency and Clinical Impact of WT1 Mutations in the Context of CEBPA-Mutated Acute Myeloid Leukemia

Hua

et al. 2021

Preprint

Cancer Biology & Therapy

“…Mutations in WT1 affect normal hematopoiesis, cell cycle, apoptosis, transcription, and cell proliferation. 5 , 14 , 15 Previous studies have reported that WT1 was associated with poor outcomes and adverse response to treatment, especially the overexpression of WT1 at diagnosis, but different studies had different definitions of WT1 overexpression due to the various detection methods etc. 10 , 11 , 16 , 17 In addition, some studies have revealed that the high expression of WT1 was related to inv(16), NPM1 and 11q23 rearrangement, while the low expression of WT1 was related to t(8; 21).…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of WT1 in the evaluation of therapeutic effect and prognosis of non-M3 acute myeloid leukemia

Yu,

Zhan,

Yan

et al. 2023

To explore the clinical significance and prognosis of acute myeloid leukemia (AML) patients with WT1 mutations.In total, the clinical data of 269 adult patients with non-M3 AML were considered retrospectively. From these patients, 153 carried WT1 mutation whereas 116 were negative. WT1 mutation positive patients were further divided into WT1 low expression and high expression groups base on the expression level of WT1 by qPCR at diagnosis (cut off: 170500). Survival and therapeutic effect analysis were performed for the above patients with different interfering factors such as co-mutations, the extent of WT1 log reduction and the chemotherapy regimens. Patients with high WT1 expression have higher rate of relapse. We can accurately identify patients with inferior outcomes when we take the following factors into consideration: the WT1 expression level at diagnosis; different prognostic factors including co-mutations (especially NPM1 and FLT3-ITD); the log reduction of WT1 after induction therapy and the risk of stratification. Idarubicin + Cytarabine (IA) regimen could reduce the expression level of WT1 after treatment, and Allo-HSCT played an important role in improving the prognosis of patients with WT1 high expression and patients with WT1 negativity. Among the relapsed patients, there existed a rising trend of WT1-MRD in advance than MFC-MRD and that of patients with continuous complete remission (CR). Different clinical background should be taken into consideration when we judge the prognosis and therapeutic effect of patients with WT1 mutations. In addition, WT1 may be an optional MRD marker, which needs regular monitoring.

“…In contrast to acute leukemia, mononuclear cells from bone marrow or peripheral blood of healthy volunteers did not express the WT1 gene at detectable levels ( Menssen et al, 1995 ; Padmakumar et al, 2021 ). Mutations in exons 7 and 9 of WT1 have been identified in acute myeloid leukemia and are related to poorer prognosis and resistance to treatment ( Aref et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Signatures in Acute Promyelocytic Leukemia Treatment and Molecular Remission

et al. 2022

Acute myeloid leukemia (AML) is an aggressive, heterogeneous group of malignancies with different clinical behaviors and different responses to therapy. For many types of cancer, finding cancer early makes it easier to treat. Identifying prognostic molecular markers and understanding their biology are the first steps toward developing novel diagnostic tools or therapies for patients with AML. In this study, we defined proteins and genes that can be used in the prognosis of different acute leukemia cases and found possible uses in diagnostics and therapy. We analyzed newly diagnosed acute leukemia cases positive for t (15; 17) (q22; q21) PML-RAR alpha, acute promyelocytic leukemia (APL). The samples of bone marrow cells were collected from patients at the diagnosis stage, as follow-up samples during standard treatment with all-trans retinoic acid, idarubicin, and mitoxantrone, and at the molecular remission. We determined changes in the expression of genes involved in leukemia cell growth, apoptosis, and differentiation. We observed that WT1, CALR, CAV1, and MYC genes’ expression in all APL patients with no relapse history was downregulated after treatment and could be potential markers associated with the pathology, thereby revealing the potential value of this approach for a better characterization of the prediction of APL outcomes.