Tumor suppressors in acute myeloid leukemia

Wallwitz, Jacqueline; Aigner, Petra; Stoiber, Dagmar

doi:10.1080/10428194.2021.1907372

Cited by 6 publications

(3 citation statements)

References 95 publications

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“…Its occurrence, development, and progression are a critical process involving multiple factors and steps [2]. The key molecular mechanism of the occurrence of AL has not been fully elucidated [3][4][5]. Epigenetics indicates the alterations of gene expression levels mediated by nongene sequence changes.…”

Section: Introductionmentioning

confidence: 99%

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Hua

Wang

et al. 2022

Applied Bionics and Biomechanics

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Purpose. Abnormal methylation of Grainyhead-like 2 (GRHL2) is associated with a substantial role in the malignant phenotype of tumor patients. Our present research is aimed at studying the abnormal expression of GRHL2 and the association of methylation in patients with acute leukemia and its relationship with prognosis. Materials and Methods. We used quantitative real-time polymerase chain reaction (qRT-PCR) for detecting the aberrant expression level of GRHL2 in 60 patients with acute leukemia and 60 normal controls. We analyzed the significant correlation between the expression level of GRHL2 with clinicopathological features and patients’ prognosis in acute leukemia using the corresponding statistical methods. Secondly, we employed qRT-PCR and Western blotting to detect the mRNA and protein levels of GRHL2 in leukemia cell lines. Next, we used methylation-specific polymerase chain reaction (MSP) technology for detecting the methylation of GRHL2 in clinical samples with acute leukemia and cell lines. Then we investigated the demethylating effect of arsenic trioxide and 5-azacitidine on the mRNA and protein expression levels of GRHL2 in cell lines of acute leukemia. Finally, we studied the effects of arsenide trioxide and 5-azacitidine on the proliferation of leukemia cells and the TGF-β signaling pathway. Results. We found a lower level of GRHL2 expression not only in acute leukemia patients but also in cell lines when compared with normal controls. At the same time, the expression level of GRHL2 in patients with acute leukemia was significantly correlated with leukocyte count, platelet count, and cytogenetic risk grouping. In addition, the lower GRHL2 expression group showed a significantly lower overall survival rate in acute leukemia patients than that of patients with a higher GRHL2 expression group. Univariate and multivariate analyses revealed that the expression of GRHL2 is an independent risk factor in acute leukemia patients. The methylation level of the GRHL2 promoter region in acute leukemia patients and cell lines was significantly higher than the normal control group, and we found the elevated mRNA and protein levels of GRHL2 in acute leukemia cell lines after the use of the demethylation drug arsenic trioxide and 5-azacitidine. At the same time, arsenide trioxide and 5-azacitidine are associated with the inhibition of cellular proliferation of acute leukemia cells and also promote the elevated expression of TGF-β signaling pathway-linked proteins, including TGF-β, Smad2, Smad3, and Smad4. Conclusion. Increased expression and methylation level of GRHL2 are closely associated with the prognosis and malignant phenotype of acute leukemia patients and play an irreplaceable role in the occurrence and development of patients with acute leukemia.

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Section: Introductionmentioning

confidence: 99%

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Hua

Wang

et al. 2022

Applied Bionics and Biomechanics

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“…Аберрантное гиперметилирование ДНК приводит к транскрипционному молчанию и инактивации генов супрессоров опухолей, тогда как гипометилирование связано с хромосомной нестабильностью и потерей импринтинга [32]. Гиперметилирование генов супрессоров опухолевого роста характерно для таких заболеваний, как лейкозы различного генеза, немелкоклеточный рак легких, колоректальный рак, рак молочной железы, предстательной железы и мочевого пузыря [33][34][35][36][37][38][39][40][41][42][43].…”

Section: метилирование днк при различных злокачественных новообразова...unclassified

Aberrations of DNA methylation in cancer

et al. 2022

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DNA methylation is a chromatin modification that plays an important role in the epigenetic regulation of gene expression. Changes in DNA methylation patterns are characteristic of many malignant neoplasms. DNA methylation is occurred by DNA methyltransferases (DNMTs), while demethylation is mediated by TET family proteins. Mutations and changes in the expression profile of these enzymes lead to DNA hypo- and hypermethylation and have a strong impact on carcinogenesis. In this review, we considered the key aspects of the mechanisms of regulation of DNA methylation and demethylation, and also analyzed the role of DNA methyltransferases and TET family proteins in the pathogenesis of various malignant neoplasms.During the preparation of the review, we used the following biomedical literature information bases: Scopus (504), PubMed (553), Web of Science (1568), eLibrary (190). To obtain full-text documents, the electronic resources of PubMed Central (PMC), Science Direct, Research Gate, CyberLeninka were used. To analyze the mutational profile of epigenetic regulatory enzymes, we used the cBioportal portal (https://www.cbioportal.org / ), data from The AACR Project GENIE Consortium (https://www.mycancergenome.org / ), COSMIC, Clinvar, and The Cancer Genome Atlas (TCGA).

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“…AML in the vast majority of paediatric patients develops de novo, whilst in adult patients AML more frequently develops from myeloproliferative neoplasms or myelodysplastic syndromes [1]. Along with age, there is often an increase in the activation of oncogenes, such as FLT3 [4], inactivation of tumour suppressor genes, such as WT1 [5], aberration of epigenetic modulators, such as TET2 [4], and decreased immune response [1]. Survival rates differ significantly between adult and paediatric patients, with one study showing a 5-year survival of ~17% in adult patients over 60 years of age [6], while survival rates in paediatric patients were around 60-75% [1].…”

Section: Introductionmentioning

confidence: 99%

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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Tumor suppressors in acute myeloid leukemia

Cited by 6 publications

References 95 publications

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Aberrations of DNA methylation in cancer

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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