Increased methylation upstream of the MEG3 promotor is observed in acute myeloid leukemia patients with better overall survival

Sellers, Zachariah Payne; Bołkuń, Łukasz; Kłoczko, Janusz; Wojtaszewska, Marzena; Lewandowski, Krzysztof; Moniuszko, Marcin; Ratajczak, Mariusz Z.; Schneider, Gabriela

doi:10.1186/s13148-019-0643-z

Cited by 25 publications

(23 citation statements)

References 48 publications

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“…MEG3 is significantly downregulated in AML patients’ tissue samples and cell lines when compared to normal controls, particularly in the Wilms’ tumor 1 (WT1) or ten–eleven translocation 2 (TET2) mutant AML patients [92,345,346]. DNA hypermethylation of CpG sites within the MEG3 promotor region can be seen in bone marrow (BM) samples from AML patients, and decreased TET2 expression level in AML patients may result in elevated MEG3 promoter methylation, which ultimately represses MEG3 expression and causes AML development [346,347]. Additionally, overexpression of MEG3 in MOLM-13 cell line inhibits cell proliferation and induces apoptosis and G0/G1 cell cycle arrest when compared with controls [345].…”

Section: Lncrnas In Hematological Malignanciesmentioning

confidence: 99%

Long Non-Coding RNA in the Pathogenesis of Cancers

Chi

Wang

et al. 2019

Cells

646

452

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The incidence and mortality rate of cancer has been quickly increasing in the past decades. At present, cancer has become the leading cause of death worldwide. Most of the cancers cannot be effectively diagnosed at the early stage. Although there are multiple therapeutic treatments, including surgery, radiotherapy, chemotherapy, and targeted drugs, their effectiveness is still limited. The overall survival rate of malignant cancers is still low. It is necessary to further study the mechanisms for malignant cancers, and explore new biomarkers and targets that are more sensitive and effective for early diagnosis, treatment, and prognosis of cancers than traditional biomarkers and methods. Long non-coding RNAs (lncRNAs) are a class of RNA transcripts with a length greater than 200 nucleotides. Generally, lncRNAs are not capable of encoding proteins or peptides. LncRNAs exert diverse biological functions by regulating gene expressions and functions at transcriptional, translational, and post-translational levels. In the past decade, it has been demonstrated that the dysregulated lncRNA profile is widely involved in the pathogenesis of many diseases, including cancer, metabolic disorders, and cardiovascular diseases. In particular, lncRNAs have been revealed to play an important role in tumor growth and metastasis. Many lncRNAs have been shown to be potential biomarkers and targets for the diagnosis and treatment of cancers. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis of certain malignant cancers, including lung, breast, liver, and colorectal cancers, as well as hematological malignancies and neuroblastoma.

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Section: Lncrnas In Hematological Malignanciesmentioning

confidence: 99%

Long Non-Coding RNA in the Pathogenesis of Cancers

Chi

Wang

et al. 2019

Cells

646

452

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“…It thus implies that DNA methylation may serve as an additional parameter in the stratification of AML patients. At a glance, many studies have already investigated the clinical implications of DNA methylation in AML (Table 1) [18,21,83,84,85,86,87,88,89,90,91,92,93,94]. In this section, we discuss the potential of DNA methylation assessment in AML diagnosis and prognosis, and in the evaluation of therapeutic efficacy.…”

Section: Clinical Implications Of Dna Methylation In Amlmentioning

confidence: 99%

Aberrant DNA Methylation in Acute Myeloid Leukemia and Its Clinical Implications

Yang

Wong

2019

IJMS

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Acute myeloid leukemia (AML) is a heterogeneous disease that is characterized by distinct cytogenetic or genetic abnormalities. Recent discoveries in cancer epigenetics demonstrated a critical role of epigenetic dysregulation in AML pathogenesis. Unlike genetic alterations, the reversible nature of epigenetic modifications is therapeutically attractive in cancer therapy. DNA methylation is an epigenetic modification that regulates gene expression and plays a pivotal role in mammalian development including hematopoiesis. DNA methyltransferases (DNMTs) and Ten-eleven-translocation (TET) dioxygenases are responsible for the dynamics of DNA methylation. Genetic alterations of DNMTs or TETs disrupt normal hematopoiesis and subsequently result in hematological malignancies. Emerging evidence reveals that the dysregulation of DNA methylation is a key event for AML initiation and progression. Importantly, aberrant DNA methylation is regarded as a hallmark of AML, which is heralded as a powerful epigenetic marker in early diagnosis, prognostic prediction, and therapeutic decision-making. In this review, we summarize the current knowledge of DNA methylation in normal hematopoiesis and AML pathogenesis. We also discuss the clinical implications of DNA methylation and the current therapeutic strategies of targeting DNA methylation in AML therapy.

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“…Over time, several research groups have shown different prognostic capabilities of expression and methylation profiling [6][7][8]. Nonetheless, most molecular biology markers used in clinical practice are represented by gene mutations, while DNA methylation and RNA expression are commonly only used within the research setting [6,[9][10][11][12]. This might be due to economic reasons, levels of evidence, and the reproducibility that can be achieved.…”

Section: Introductionmentioning

confidence: 99%

The Influence of Methylating Mutations on Acute Myeloid Leukemia: Preliminary Analysis on 56 Patients

et al. 2020

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Acute myeloid leukemia (AML) is a hematologic malignancy characterized by abnormal proliferation and a lack of differentiation of myeloid blasts. Considering the dismal prognosis this disease presents, several efforts have been made to better classify it and offer a tailored treatment to each subtype. This has been formally done by the World Health Organization (WHO) with the AML classification schemes from 2008 and 2016. Nonetheless, there are still mutations that are not currently included in the WHO AML classification, as in the case of some mutations that influence methylation. In this regard, the present study aimed to determine if some of the mutations that influence DNA methylation can be clustered together regarding methylation, expression, and clinical profile. Data from the TCGA LAML cohort were downloaded via cBioPortal. The analysis was performed using R 3.5.2, and the necessary packages for classical statistics, dimensionality reduction, and machine learning. We included only patients that presented mutations in DNMT3A, TET2, IDH1/2, ASXL1, WT1, and KMT2A. Afterwards, mutations that were present in too few patients were removed from the analysis, thus including a total of 57 AML patients. We observed that regarding expression, methylation, and clinical profile, patients with mutated TET2, IDH1/2, and WT1 presented a high degree of similarity, indicating the equivalence that these mutations present between themselves. Nonetheless, we did not observe this similarity between DNMT3A- and KMT2A-mutated AML. Moreover, when comparing the hypermethylating group with the hypomethylating one, we also observed important differences regarding expression, methylation, and clinical profile. In the current manuscript we offer additional arguments for the similarity of the studied hypermethylating mutations and suggest that those should be clustered together in further classifications. The hypermethylating and hypomethylating groups formed above were shown to be different from each other considering overall survival, methylation profile, expression profile, and clinical characteristics. In this manuscript, we present additional arguments for the similarity of the effect generated by TET2, IDH1/2, and WT1 mutations in AML patients. Thus, we hypothesize that hypermethylating mutations skew the AML cells to a similar phenotype with a possible sensitivity to hypermethylating agents.

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Increased methylation upstream of the MEG3 promotor is observed in acute myeloid leukemia patients with better overall survival

Cited by 25 publications

References 48 publications

Long Non-Coding RNA in the Pathogenesis of Cancers

Long Non-Coding RNA in the Pathogenesis of Cancers

Aberrant DNA Methylation in Acute Myeloid Leukemia and Its Clinical Implications

The Influence of Methylating Mutations on Acute Myeloid Leukemia: Preliminary Analysis on 56 Patients

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