scholarly journals Aberrant DNA Methylation in Acute Myeloid Leukemia and Its Clinical Implications

2019 ◽  
Vol 20 (18) ◽  
pp. 4576 ◽  
Author(s):  
Xianwen Yang ◽  
Molly Pui Man Wong ◽  
Ray Kit Ng
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Epigenetic Modification ◽  
Critical Role ◽  
Genetic Alterations ◽  
Dna Methyltransferases ◽  
Clinical Implications ◽  
Aberrant Dna Methylation ◽  
Acute Myeloid

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.

Genetic alterations and their clinical implications in older patients with acute myeloid leukemia

Leukemia ◽  
2016 ◽  
Vol 30 (7) ◽  
pp. 1485-1492 ◽  
Author(s):  
C-H Tsai ◽  
H-A Hou ◽  
J-L Tang ◽  
C-Y Liu ◽  
C-C Lin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Genetic Alterations ◽  
Clinical Implications ◽  
Acute Myeloid

Aberrant DNA methylation of acute myeloid leukemia and colorectal cancer in a Chinese pedigree with a MLL3 germline mutation

Tumor Biology ◽  
2016 ◽  
Vol 37 (9) ◽  
pp. 12609-12618 ◽  
Author(s):  
Fuhua Yang ◽  
Qiang Gong ◽  
Wentao Shi ◽  
Yunding Zou ◽  
Jingmin Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Germline Mutation ◽  
Myeloid Leukemia ◽  
Aberrant Dna Methylation ◽  
Acute Myeloid

scholarly journals Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia

10.1186/gm551 ◽  
2014 ◽  
Vol 6 (4) ◽  
pp. 34 ◽  
Author(s):  
Miriam Sonnet ◽  
Rainer Claus ◽  
Natalia Becker ◽  
Manuela Zucknick ◽  
Jana Petersen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Aberrant Dna Methylation ◽  
Acute Myeloid

scholarly journals Functions of RNA N6-methyladenosine modification in acute myeloid leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xue Zheng ◽  
Yuping Gong
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nuclear Export ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Gene Expression Regulation ◽  
Epigenetic Modification ◽  
Hematologic Malignancy ◽  
Critical Role ◽  
Leukemia Cell ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a hematologic malignancy with an unfavorable prognosis. A better understanding of AML pathogenesis and chemotherapy resistance at the molecular level is essential for the development of new therapeutic strategies. Apart from DNA methylation and histone modification, RNA epigenetic modification, another layer of epigenetic modification, also plays a critical role in gene expression regulation. Among the more than 150 kinds of RNA epigenetic modifications, N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in eukaryotes and is involved in various biological processes, such as circadian rhythms, adipogenesis, T cell homeostasis, spermatogenesis, and the heat shock response. As a reversible and dynamic modification, m6A is deposited on specific target RNA molecules by methyltransferases and is removed by demethylases. Moreover, m6A binding proteins recognize m6A modifications, influencing RNA splicing, stability, translation, nuclear export, and localization at the posttranscriptional level. Emerging evidence suggests that dysregulation of m6A modification is involved in tumorigenesis, including that of AML. In this review, we summarize the most recent advances regarding the biological functions and molecular mechanisms of m6A RNA methylation in normal hematopoiesis, leukemia cell proliferation, apoptosis, differentiation, therapeutic resistance, and leukemia stem cell/leukemia initiating cell (LSC/LIC) self-renewal. In addition, we discuss how m6A regulators are closely correlated with the clinical features of AML patients and may serve as new biomarkers and therapeutic targets for AML.

scholarly journals DNA Methylation Events as Markers for Diagnosis and Management of Acute Myeloid Leukemia and Myelodysplastic Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Geórgia Muccillo Dexheimer ◽  
Jayse Alves ◽  
Laura Reckziegel ◽  
Gabrielle Lazzaretti ◽  
Ana Lucia Abujamra
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Epigenetic Modification ◽  
Dynamic Change ◽  
Cellular Transformation ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Acute Myeloid

During the onset and progression of hematological malignancies, many changes occur in cellular epigenome, such as hypo- or hypermethylation of CpG islands in promoter regions. DNA methylation is an epigenetic modification that regulates gene expression and is a key event for tumorigenesis. The continuous search for biomarkers that signal early disease, indicate prognosis, and act as therapeutic targets has led to studies investigating the role of DNA in cancer onset and progression. This review focuses on DNA methylation changes as potential biomarkers for diagnosis, prognosis, response to treatment, and early toxicity in acute myeloid leukemia and myelodysplastic syndrome. Here, we report that distinct changes in DNA methylation may alter gene function and drive malignant cellular transformation during several stages of leukemogenesis. Most of these modifications occur at an early stage of disease and may predict myeloid/lymphoid transformation or response to therapy, which justifies its use as a biomarker for disease onset and progression. Methylation patterns, or its dynamic change during treatment, may also be used as markers for patient stratification, disease prognosis, and response to treatment. Further investigations of methylation modifications as therapeutic biomarkers, which may correlate with therapeutic response and/or predict treatment toxicity, are still warranted.

Origins of aberrant DNA methylation in acute myeloid leukemia

Leukemia ◽  
2013 ◽  
Vol 28 (1) ◽  
pp. 1-14 ◽  
Author(s):  
T Schoofs ◽  
W E Berdel ◽  
C Müller-Tidow
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Aberrant Dna Methylation ◽  
Acute Myeloid

scholarly journals Genome-wide DNA Methylation Analysis in Pediatric Acute Myeloid Leukemia

2022 ◽  
Author(s):  
Genki Yamato ◽  
Tomoko Kawai ◽  
Norio Shiba ◽  
Junji Ikeda ◽  
Yusuke Hara ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Genetic Alterations ◽  
Binding Motif ◽  
Cpg Sites ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Acute Myeloid

We investigated genome-wide DNA methylation patterns in 64 pediatric patients with acute myeloid leukemia (AML). Based on unsupervised clustering with 567 most variably methylated CpG sites, patients were categorized into four clusters associated with genetic alterations. Clusters 1 and 3 were characterized by the presence of known favorable prognostic factors, such as RUNX1-RUNX1T1 fusion and KMT2A rearrangement with low MECOM expression, and biallelic CEBPA mutations (all 8 patients), respectively. Clusters 2 and 4 comprised patients exhibiting molecular features associated with adverse outcomes, namely FLT3-ITD, KMT2A-PTD, and high PRDM16 expression. Depending on the methylation values of the 1243 CpG sites that were significantly different between FLT3-ITD positive and negative AML, patients were categorized into three clusters: A, B, and C. The STAT5-binding motif was most frequently found close to the 1,243 CpG sites. All eight patients with FLT3-ITD in Cluster A harbored high PRDM16 expression and experienced adverse events, whereas only one of seven patients with FLT3-ITD in the other clusters experienced adverse events. PRDM16 expression levels were also related to DNA methylation patterns, which were drastically changed at the cutoff value of PRDM16/ABL1 = 0.10. The assay for transposase-accessible chromatin sequencing of AMLs supported enhanced chromatin accessibilities around genomic regions, such as HOXB cluster genes, SCHIP1, and PRDM16, which were associated with DNA methylation changes in AMLs with FLT3-ITD and high PRDM16 expression. Our results suggest that DNA methylation levels at specific CpG sites are useful to support genetic alterations and gene expression patterns of patients with pediatric AML.

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