Relationship between Altered miRNA Expression and DNA Methylation of the DLK1-DIO3 Region in Azacitidine-Treated Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

Merkerová, Michaela Dostálová; Remešová, Hana; Krejčík, Zdeněk; Loudova, Nikoleta; Hruštincová, Andrea; Szikszai, Katarína; Čermák, Jaroslav; Jonášová, Anna; Beličková, Monika

doi:10.3390/cells7090138

Cited by 16 publications

(16 citation statements)

References 33 publications

(51 reference statements)

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“…In our recent study, we demonstrated increased expression of 14q32 miRNAs in CD34+ cells in advanced stages of MDS and in AML-MRC and associated this elevation with poor outcome. Moreover, the increased intracellular levels of 14q32 miRNAs were reduced after AZA treatment [73]. Based on the present data, it seems that the levels of 14q32 miRNAs have opposite trends in HSCs and in plasma in different stages of the disease, i.e., these miRNAs are released into the extracellular environment in early, pro-apoptotic stages of MDS but are retained intrinsically along with disease progression.…”

Section: Discussionmentioning

confidence: 54%

Circulating Small Noncoding RNAs Have Specific Expression Patterns in Plasma and Extracellular Vesicles in Myelodysplastic Syndromes and Are Predictive of Patient Outcome

Hruštincová

Krejčík

Kundrat

et al. 2020

Cells

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Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders with large heterogeneity at the clinical and molecular levels. As diagnostic procedures shift from bone marrow biopsies towards less invasive techniques, circulating small noncoding RNAs (sncRNAs) have become of particular interest as potential novel noninvasive biomarkers of the disease. We aimed to characterize the expression profiles of circulating sncRNAs of MDS patients and to search for specific RNAs applicable as potential biomarkers. We performed small RNA-seq in paired samples of total plasma and plasma-derived extracellular vesicles (EVs) obtained from 42 patients and 17 healthy controls and analyzed the data with respect to the stage of the disease, patient survival, response to azacitidine, mutational status, and RNA editing. Significantly higher amounts of RNA material and a striking imbalance in RNA content between plasma and EVs (more than 400 significantly deregulated sncRNAs) were found in MDS patients compared to healthy controls. Moreover, the RNA content of EV cargo was more homogeneous than that of total plasma, and different RNAs were deregulated in these two types of material. Differential expression analyses identified that many hematopoiesis-related miRNAs (e.g., miR-34a, miR-125a, and miR-150) were significantly increased in MDS and that miRNAs clustered on 14q32 were specifically increased in early MDS. Only low numbers of circulating sncRNAs were significantly associated with somatic mutations in the SF3B1 or DNMT3A genes. Survival analysis defined a signature of four sncRNAs (miR-1237-3p, U33, hsa_piR_019420, and miR-548av-5p measured in EVs) as the most significantly associated with overall survival (HR = 5.866, p < 0.001). In total plasma, we identified five circulating miRNAs (miR-423-5p, miR-126-3p, miR-151a-3p, miR-125a-5p, and miR-199a-3p) whose combined expression levels could predict the response to azacitidine treatment. In conclusion, our data demonstrate that circulating sncRNAs show specific patterns in MDS and that their expression changes during disease progression, providing a rationale for the potential clinical usefulness of circulating sncRNAs in MDS prognosis. However, monitoring sncRNA levels in total plasma or in the EV fraction does not reflect one another, instead, they seem to represent distinctive snapshots of the disease and the data should be interpreted circumspectly with respect to the type of material analyzed.

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Section: Discussionmentioning

confidence: 54%

Circulating Small Noncoding RNAs Have Specific Expression Patterns in Plasma and Extracellular Vesicles in Myelodysplastic Syndromes and Are Predictive of Patient Outcome

Hruštincová

Krejčík

Kundrat

et al. 2020

Cells

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“…Thus, there is a need for new biomarkers to better improve patient prognosis [12, 13]. Several other studies had identified DNA methylation gene as prognostic biomarkers of nasopharyngeal carcinoma and acute myeloid leukemia [14, 15]. In the current field of TETs, tumor size, gene mutation, protein expression, and miRNA had been reported to affect the prognosis of patients with TETs and potentially be used as prognostic biomarkers for TETs [15, 16].…”

Section: Discussionmentioning

confidence: 99%

“…Several other studies had identified DNA methylation gene as prognostic biomarkers of nasopharyngeal carcinoma and acute myeloid leukemia [14, 15]. In the current field of TETs, tumor size, gene mutation, protein expression, and miRNA had been reported to affect the prognosis of patients with TETs and potentially be used as prognostic biomarkers for TETs [15, 16]. However, targeting DNA methylation sites as prognostic biomarkers for TETs have not been explored, and our current study is the first to report DNA methylation sites as biomarkers for the prognosis of patients with TETs.…”

Section: Discussionmentioning

confidence: 99%

Discovery and validation of DNA methylation markers for overall survival prognosis in patients with thymic epithelial tumors

Yuan²,

Xiao

et al. 2019

Clin Epigenet

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Background The current prognosis of thymic epithelial tumors (TETs) is according to the World Health Organization (WHO) histologic classification and the Masaoka staging system. These methods of prognosis have certain limitations in clinical application and there is a need to seek new method for determining the prognosis of patients with TETs. To date, there have been no studies done on the use of DNA methylation biomarkers for prognosis of TETs. The present study was therefore carried out to identify DNA methylation biomarkers that can determine the overall survival in patients with TETs. Methods Bioinformatic analysis of TCGA 450 K methylation array data, transcriptome sequencing data, WHO histologic classification and Masaoka staging system was performed to identify differentially expressed methylation sites between thymoma and thymic carcinoma as well as the different DNA methylation sites associated with the overall survival in patients with TETs. Using pyrosequencing, 4 different methylation sites (cg05784862, cg07154254, cg02543462, and cg06288355) were sequenced from tumor tissues of 100 Chinese patients with TETs. A prognostic model for TETs was constructed using these four methylation sites. Results The TCGA dataset showed 5155 and 6967 hyper- and hypomethylated CpG sites in type A–B3 group and type C group, respectively, of which 3600 were located within the gene promoter regions. One hundred thirty-four genes were silenced by promoter hypermethylation and 174 mRNAs were upregulated. Analysis of univariate and multivariate Cox regression showed significant association between the methylation levels of 187 sites and the overall survival in patients with TETs. cg05784862( KSR1 ), cg07154254( ELF3 ), cg02543462( ILRN ), and cg06288355( RAG1 ) were identified as independent prognostic factors for overall survival in patients with TETs after adjusting for Masaoka staging in 100 Chinese patients. The prognostic model which consists of the four abovementioned genes had higher accuracy for predicting the 5-year overall survival in patients with TETs as compared to the Masaoka clinical staging. (Time-dependent ROC analysis AUC 1.000 vs 0.742, P = 2.7 × 10 −6 ). Conclusions The methylation levels of cg05784862( KSR1 ), cg07154254( ELF3 ), cg02543462( ILRN ), and cg06288355( RAG1 ) sites are associated with the progression of TETs and may serve as new biomarkers for predicting the overall survival in patients with TETs. Electronic supplementary material The online version of this article (10.1186/s13148-019-0619-z

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“…To confirm the impact of the identified gene markers on prognosis and HMA response, we applied the gene set-level scores (i.e., the mean expression of leading edge genes of 20 GO terms in Table 2) in independent data sets. We obtained publicly available gene expression profiles of 123 MDS patients with overall survival (GSE58831) 37 and 32 patients with AZA treatment history (13 responders and 19 non-responders; GSE77750) 38,39 . For survival (GSE58831), MDS patients whose gene expression profiles resembled those of AZA responders in our study ('responder-like') showed better survival (green in Fig.…”

Section: Validation Of Azacitidine Sensitivity Signatures In Independmentioning

confidence: 99%

Gene expression signatures associated with sensitivity to azacitidine in myelodysplastic syndromes

Kim

Park

Choi

et al. 2020

Sci Rep

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Allogeneic stem cell transplantation is currently the only curative treatment option for myelodysplastic syndromes (MDS). Pre-transplant debulking treatment have been employed for advanced MDS and we previously reported that marrow response (blast ≤ 5%) following the bridging therapy with hypomethylating agent was an independent favorable factor for survival; however, it is still not clear which patients will respond to hypomethylating agent and which genomic features can predict the response. In this study, we performed RNAseq for 23 MDS patients among which 14 (61%) and 9 (39%) patients showed marrow complete remission and primary resistance to azacitidine, respectively. Differential expression-based analyses of treatment-naive, baseline gene expression profiles revealed that molecular functions representing mitochondria and apoptosis were up-regulated in responders. In contrast, we identified genes involved in the Wnt pathway were relatively up-regulated in non-responders. In independent validation cohorts of MDS patients, the expression of gene sets specific to non-responders and responders distinguished the patients with favorable prognosis and those responded to azacitidine highlighting the prognostic and predictive implication. In addition, a systems biology approach identified genes involved in ubiquitination, such as UBC and PFDN2, which may be key players in the regulation of differential gene expression in treatment responders and non-responders. Taken together, identifying the gene expression signature may advance our understanding of the molecular mechanisms of azacitidine and may also serve to predict patient responses to drug treatment.

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Relationship between Altered miRNA Expression and DNA Methylation of the DLK1-DIO3 Region in Azacitidine-Treated Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

Cited by 16 publications

References 33 publications

Circulating Small Noncoding RNAs Have Specific Expression Patterns in Plasma and Extracellular Vesicles in Myelodysplastic Syndromes and Are Predictive of Patient Outcome

Circulating Small Noncoding RNAs Have Specific Expression Patterns in Plasma and Extracellular Vesicles in Myelodysplastic Syndromes and Are Predictive of Patient Outcome

Discovery and validation of DNA methylation markers for overall survival prognosis in patients with thymic epithelial tumors

Gene expression signatures associated with sensitivity to azacitidine in myelodysplastic syndromes

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