A study on DNA methylation status in promoter region of p15 gene in patients of acute myeloid leukemia and myelodysplastic syndrome

Somanna, Sampath; Misra, Pratibha; Yadav, Sandeep Kumar; Sharma, Sanjeevan; Somasundaram, Venkatesan

doi:10.1016/j.mjafi.2021.04.014

Cited by 3 publications

(3 citation statements)

References 25 publications

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“…Epigenetics causes aberrant gene expression by heritable factors that do not alter the sequence of DNA itself, including DNA methylation (cytopyrimidine methylation and hydroxymethylation), histone modification, and noncoding RNA regulation [ 18 ]. DNA methylation, in particular, is a key signal that regulates gene expression during eukaryotic cell development [ 19 ].…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Hua

Wang

et al. 2022

Applied Bionics and Biomechanics

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“… 90 For example, in one study, patients with hypermethylated CDKN2A had significantly shorter survival (median = 21.7 months) than patients without CDKN2A hypermethylation (median = 62.5 months; p = 0.0001, log-rank test). 91 In Acute Myeloid Leukaemia (AML), CDKN2B methylation has been reported in 49–100% of patients, depending on the population analysed, 92 and has also been found to correlate with poor survival. 93…”

Section: Aberrant Dna Methylation and Carcinogenesismentioning

confidence: 99%

“…Demethylating therapies have been recommended as a therapeutic strategy for AML patients with CDKN2B methylation. 92 This approach has demonstrated success in a colon cancer cell line, where the DNMT1 inhibitor decitabine could cause demethylation of CDKN2A , which appeared to trigger senescence of cancer cells. 96 However, it should be noted that DNMT1 inhibitors like decitabine cause global hypomethylation in cells; thus, it would be difficult to assign their efficacy to demethylation of a single gene or locus.…”

Section: Aberrant Dna Methylation and Carcinogenesismentioning

confidence: 99%

The role of aberrant DNA methylation in cancer initiation and clinical impacts

Geissler,

Nesic,

Kondrashova

et al. 2024

Ther Adv Med Oncol

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Epigenetic alterations, including aberrant DNA methylation, are now recognized as bone fide hallmarks of cancer, which can contribute to cancer initiation, progression, therapy responses and therapy resistance. Methylation of gene promoters can have a range of impacts on cancer risk, clinical stratification and therapeutic outcomes. We provide several important examples of genes, which can be silenced or activated by promoter methylation and highlight their clinical implications. These include the mismatch DNA repair genes MLH1 and MSH2, homologous recombination DNA repair genes BRCA1 and RAD51C, the TERT oncogene and genes within the P15/P16/RB1/E2F tumour suppressor axis. We also discuss how these methylation changes might occur in the first place – whether in the context of the CpG island methylator phenotype or constitutional DNA methylation. The choice of assay used to measure methylation can have a significant impact on interpretation of methylation states, and some examples where this can influence clinical decision-making are presented. Aberrant DNA methylation patterns in circulating tumour DNA (ctDNA) are also showing great promise in the context of non-invasive cancer detection and monitoring using liquid biopsies; however, caution must be taken in interpreting these results in cases where constitutional methylation may be present. Thus, this review aims to provide researchers and clinicians with a comprehensive summary of this broad, but important subject, illustrating the potentials and pitfalls of assessing aberrant DNA methylation in cancer.

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Targeting DNA Methylation in Leukemia, Myelodysplastic Syndrome, and Lymphoma: A Potential Diagnostic, Prognostic, and Therapeutic Tool

Kalinkova

Sevcikova

Stevurkova

et al. 2022

IJMS

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DNA methylation represents a crucial mechanism of epigenetic regulation in hematologic malignancies. The methylation process is controlled by specific DNA methyl transferases and other regulators, which are often affected by genetic alterations. Global hypomethylation and hypermethylation of tumor suppressor genes are associated with hematologic cancer development and progression. Several epi-drugs have been successfully implicated in the treatment of hematologic malignancies, including the hypomethylating agents (HMAs) decitabine and azacytidine. However, combinations with other treatment modalities and the discovery of new molecules are still the subject of research to increase sensitivity to anti-cancer therapies and improve patient outcomes. In this review, we summarized the main functions of DNA methylation regulators and genetic events leading to changes in methylation landscapes. We provide current knowledge about target genes with aberrant methylation levels in leukemias, myelodysplastic syndromes, and malignant lymphomas. Moreover, we provide an overview of the clinical trials, focused mainly on the combined therapy of HMAs with other treatments and its impact on adverse events, treatment efficacy, and survival rates among hematologic cancer patients. In the era of precision medicine, a transition from genes to their regulation opens up the possibility of an epigenetic-based approach as a diagnostic, prognostic, and therapeutic tool.

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A study on DNA methylation status in promoter region of p15 gene in patients of acute myeloid leukemia and myelodysplastic syndrome

Cited by 3 publications

References 25 publications

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

The role of aberrant DNA methylation in cancer initiation and clinical impacts

Targeting DNA Methylation in Leukemia, Myelodysplastic Syndrome, and Lymphoma: A Potential Diagnostic, Prognostic, and Therapeutic Tool

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