The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Chiereghin, Chiara; Travaglino, Erica; Zampini, Matteo; Saba, Elena; Saitta, Claudia; Riva, E.; Bersanelli, Matteo; Porta, Matteo Giovanni Della

doi:10.3390/genes12081144

Cited by 23 publications

(22 citation statements)

References 47 publications

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“…In the tumor, researchers paid crucial attention to epigenetic regulation that critically regulates gene expression. Abnormal DNA methylation as epigenetic markers indicates a novel research avenue for the diagnosis, treatment, and prognosis of tumors [ 20 ]. At present, epigenetics is mainly monitored by DNA methylation and mRNA detection [ 21 ].…”

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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“…MDS is a kind of clonal disorder in hematopoietic stem cell progenitors, with ineffective hematopoiesis, morphologic dysplasia, and a high risk of acute myeloid leukemia (AML). Almost 90% of MDS patients were detected carrying a somatic mutation in at least one gene, and the mutation genes were mainly implicated in the pathways of RNA splicing, DNA damage response, epigenetic regulators, signal transduction, and transcription factors (11). Werner syndrome patients with WRN mutations were easy to obtain p53 gene mutations or related chromosomal abnormalities, and this was different from other MDS/AML patients' changes in cellular or molecular genetic material.…”

Section: Discussionmentioning

confidence: 97%

Case Report: A novel WRN mutation in Werner syndrome patient with diabetic foot disease and myelodysplastic syndrome

et al. 2022

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Werner syndrome is an autosomal recessive rare disease caused by a WRN gene mutation, which is rarely reported in the Chinese population. We report the clinical and genetic data of a Chinese patient with Werner syndrome. The proband was a 40-year-old male patient who presented with diabetic foot ulcers, accompanied by short stature, cataracts, hypogonadism, and hair thinning, and myelodysplastic syndrome (MDS) occurred after 18 months. Genetic sequencing showed there were compound heterozygous mutations as c.3384-1G>C and c.3744dupA in the WRN gene. The c.3744dupA mutation is a novel pathogenic variation for Werner syndrome.

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“…Myelodysplastic syndromes can be considered as a representative premalignant hematopoietic disorder that can progress towards AML. A number of publications showed the heterogenicity of factors that could be involved in the inadequate hematopoiesis, dysplastic hematopoietic cells, and bone marrow stromal defects [ 3 , 4 , 5 , 27 ]. Among these, several studies have found evidence of the involvement of free radicals in a wide variety of hematological neoplasms [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, factors that determining MDS etiology and its progression to AML are not clarified; however, several authors suggest tumor genetic alterations in genes that regulate cellular proliferation, survival, and differentiation on hematopoietic stem cell [ 3 ]. In this line, complex karyotypes and somatic mutations associated with molecular risk are important risk factors related to advances stages of the disease and progression to AML [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of 5-Azacitidine Treatment on Redox Status and Inflammatory Condition in MDS Patients

et al. 2022

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This study focused on the impact of the treatment with the hypomethylating agent 5-azacitidine on the redox status and inflammation in 24 MDS patients. Clinical and genetic features of MDS patients were recorded, and peripheral blood samples were used to determine the activity of the endogenous antioxidant defense system (superoxide dismutase, SOD; catalase, CAT; glutathion peroxidase, GPx; and reductase, GRd, activities), markers of oxidative damage (lipid peroxidation, LPO, and advanced oxidation protein products, AOPP). Moreover, pro-inflammatory cytokines and plasma nitrite plus nitrate levels as markers of inflammation, as well as CoQ10 plasma levels, were also measured. Globally, MDS patients showed less redox status in terms of a reduction in the GSSG/GSH ratio and in the LPO levels, as well as increased CAT activity compared with healthy subjects, with no changes in SOD, GPx, and GRd activities, or AOPP levels. When analyzing the evolution from early to advanced stages of the disease, we found that the GPx activity, GSSG/GSH ratio, LPO, and AOPP increased, with a reduction in CAT. GPx changes were related to the presence of risk factors such as high-risk IPSS-R or mutational score. Moreover, there was an increase in IL-2, IL-6, IL-8, and TNF-α plasma levels, with a further increase of IL-2 and IL-10 from early to advanced stages of the disease. However, we did not observe any association between inflammation and oxidative stress. Finally, 5-azacitidine treatment generated oxidative stress in MDS patients, without affecting inflammation levels, suggesting that oxidative status and inflammation are two independent processes.

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The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Cited by 23 publications

References 47 publications

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Case Report: A novel WRN mutation in Werner syndrome patient with diabetic foot disease and myelodysplastic syndrome

Effect of 5-Azacitidine Treatment on Redox Status and Inflammatory Condition in MDS Patients

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