The Prognostic Impact of WT1 Expression Levels, Mutations, and SNP rs16754 in AML Patients: A Retrospective Cohort Study

Rostami, Shahrbano; Kazemi, Ahmad; Chahardouli, Bahram; Mohammadi, Saeed; Nikbakht, Mohsen; Alizadeh, Nasrin; Mousavi, Azam Sadat; Ardestani, Majid Teremmahi

doi:10.30699/jambs.29.133.109

Cited by 2 publications

(15 citation statements)

References 27 publications

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“…AML development includes multistep events associated with point mutations, as well as chromosomal aberrations [ 2 ]. Mutations in genes encoding Wilms tumor 1 ( WT1 ), nucleophosmin ( NPM1 ), FMS-like tyrosine kinase-3 ( FLT3 ), and CCAAT/enhancer-binding protein alpha ( CEBPA ) affect the pathogenesis of AML [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…The WT1 gene may possess both tumor suppressor and oncogenic functions in childhood Wilms tumors and leukemias, respectively [ 6 ]. WT1 gene mutations are found in 6–15% of newly diagnosed AML patients [ 3 ]. Hot spots were described in two exons (7 and 9), in which loss of function mutations can occur [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…The alterations of the WT1 gene are associated with younger age, as well as the coexistence of FLT3 and CEBPA mutations [ 7 ]. The changes in the WT1 gene sequence may affect its expression [ 3 ]. The role of WT1 mutations in the pathogenesis of AML remains controversial [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…The changes in the WT1 gene sequence may affect its expression [ 3 ]. The role of WT1 mutations in the pathogenesis of AML remains controversial [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Among many variants present in the WT1 gene, special attention has been paid to the single nucleotide polymorphism rs16754 located in exon 7 (at nucleotide 1297A>G) [ 8 ]. Some studies have suggested that rs16754 can be a negative prognostic factor in AML [ 3 , 9 ]. The prognosis in AML is affected adversely by WT1 gene overexpression [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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WT1 Gene Mutations, rs16754 Variant, and WT1 Overexpression as Prognostic Factors in Acute Myeloid Leukemia Patients

Koczkodaj

Zmorzyński

Grygalewicz

et al. 2022

JCM

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(1) Background: The aim of our study was the complex assessment of WT1 variants and their expression in relation to chromosomal changes and molecular prognostic markers in acute myeloid leukemia (AML). It is the first multidimensional study in Polish AML patients; (2) Methods: Bone marrow aspirates of 90 AML patients were used for cell cultures (banding techniques and fluorescence in situ hybridization), and to isolate DNA (WT1 genotyping, array comparative genomic hybridization), and RNA (WT1 expression). Peripheral blood samples from 100 healthy blood donors were used to analyze WT1 rs16754; (3) Results: Allele frequency and distribution of WT1 variant rs16754 (A;G) did not differ significantly among AML patients and controls. Higher expression of WT1 gene was observed in AA genotype (of rs16754) in comparison with GA or GG genotypes—10,556.7 vs. 25,836.5 copies (p = 0.01), respectively. WT1 mutations were more frequent in AML patients under 65 years of age (p < 0.0001) and affected relapse-free survival (RFS). The presence of NPM1 or CEBPA mutations decreased the risk of WT1 mutation presence, odds ratio (OR) = 0.11, 95% CI 0.02–0.46, p = 0.002 or OR = 0.05, 95% CI 0.006–0.46, p = 0.002, respectively. We observed significantly higher WT1 expression in AML CD34+ vs. CD34−, −20,985 vs. 8304 (p = 0.039), respectively. The difference in WT1 expression between patients with normal and abnormal karyotype was statistically insignificant; (4) Conclusions: WT1 gene expression and its rs16754 variant at diagnosis did not affect AML outcome. WT1 mutation may affect RFS in AML.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The changes in the WT1 gene sequence may affect its expression [ 3 ]. The role of WT1 mutations in the pathogenesis of AML remains controversial [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

WT1 Gene Mutations, rs16754 Variant, and WT1 Overexpression as Prognostic Factors in Acute Myeloid Leukemia Patients

Koczkodaj

Zmorzyński

Grygalewicz

et al. 2022

JCM

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A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis

Morris

Ghazi

Fletcher

et al. 2023

IJMS

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Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies with age with associated differences in incidence, as well as the frequency of cytogenetic change and somatic mutations. In addition, 5-year survival rates in paediatrics are 60–75% but fall to 5–15% in older AML patients. This systematic review aimed to determine whether the altered genes in AML affect the same molecular pathways, indifferent of patient age, and, therefore, whether patients could benefit from the repurposing drugs or the use of the same immunotherapeutic strategies across age boundaries to prevent relapse. Using a PICO framework and PRISMA-P checklist, relevant publications were identified using five literature databases and assessed against an inclusion criteria, leaving 36 articles, and 71 targets for therapy, for further analysis. QUADAS-2 was used to determine the risk of bias and perform a quality control step. We then priority-ranked the list of cancer antigens based on predefined and pre-weighted objective criteria as part of an analytical hierarchy process used for dealing with complex decisions. This organized the antigens according to their potential to act as targets for the immunotherapy of AML, a treatment that offers an opportunity to remove residual leukaemia cells at first remission and improve survival rates. It was found that 80% of the top 20 antigens identified in paediatric AML were also within the 20 highest scoring immunotherapy targets in adult AML. To analyse the relationships between the targets and their link to different molecular pathways, PANTHER and STRING analyses were performed on the 20 highest scoring immunotherapy targets for both adult and paediatric AML. There were many similarities in the PANTHER and STRING results, including the most prominent pathways being angiogenesis and inflammation mediated by chemokine and cytokine signalling pathways. The coincidence of targets suggests that the repurposing of immunotherapy drugs across age boundaries could benefit AML patients, especially when used in combination with conventional therapies. However, due to cost implications, we would recommend that efforts are focused on ways to target the highest scoring antigens, such as WT1, NRAS, IDH1 and TP53, although in the future other candidates may prove successful.

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The Prognostic Impact of WT1 Expression Levels, Mutations, and SNP rs16754 in AML Patients: A Retrospective Cohort Study

Cited by 2 publications

References 27 publications

WT1 Gene Mutations, rs16754 Variant, and WT1 Overexpression as Prognostic Factors in Acute Myeloid Leukemia Patients

WT1 Gene Mutations, rs16754 Variant, and WT1 Overexpression as Prognostic Factors in Acute Myeloid Leukemia Patients

A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis

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