Origins of aberrant DNA methylation in acute myeloid leukemia

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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Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-17-0235 ◽

2017 ◽

Vol 23 (20) ◽

pp. 6254-6266 ◽

Cited By ~ 12

Author(s):

Na Shen ◽

Fei Yan ◽

Jiuxia Pang ◽

Na Zhao ◽

Naseema Gangat ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Tyrosine Kinases ◽

Myeloid Leukemia ◽

Receptor Tyrosine Kinases ◽

Aberrant Dna Methylation ◽

Acute Myeloid

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Profiling of aberrant DNA methylation in acute myeloid leukemia reveals subclasses of CG-rich regions with epigenetic or genetic association

Leukemia ◽

10.1038/s41375-018-0165-2 ◽

2018 ◽

Vol 33 (1) ◽

pp. 26-36 ◽

Cited By ~ 7

Author(s):

Claudia Gebhard ◽

Dagmar Glatz ◽

Lucia Schwarzfischer ◽

Julia Wimmer ◽

Sebastian Stasik ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Genetic Association ◽

Myeloid Leukemia ◽

Aberrant Dna Methylation ◽

Acute Myeloid

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Evaluation of acute myeloid leukemia blast percentage on MethylC-Capture Sequencing results

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00219-0 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Erna Yang ◽

Desheng Gong ◽

Wei Guan ◽

Jieying Li ◽

Xuefeng Gao ◽

...

Keyword(s):

Dna Methylation ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Methylation Level ◽

Myeloid Leukemia ◽

Promoter Regions ◽

Aberrant Dna Methylation ◽

Next Generation Sequencing Ngs ◽

Capture Sequencing ◽

Acute Myeloid

AbstractAberrant DNA methylation is often related to the diagnosis, prognosis, and therapeutic response of acute myeloid leukemia (AML); however, relevant studies on the relationship between bone marrow myeloblast percentage and the DNA methylation level in AML have not been reported. We evaluated the effects of AML blast percentage on DNA methylation level using the MethylC-capture sequencing (MCC-Seq) approach based on next-generation sequencing (NGS) and found that the methylation level of both genome-wide and promoter regions significantly increased when the percentage of AML blasts reached ≥ 40%, indicating that an accurate DNA methylation level in cancer cells can be obtained when the bone marrow samples of AML patients have more than 40% myeloblasts.

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Faculty Opinions recommendation of DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1528964.1017064 ◽

2010 ◽

Author(s):

Lee Grimes

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Acute Myeloid

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Identification and validation of obesity-related gene LEP methylation as a prognostic indicator in patients with acute myeloid leukemia

Clinical Epigenetics ◽

10.1186/s13148-021-01013-9 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Ting-juan Zhang ◽

Zi-jun Xu ◽

Yu Gu ◽

Ji-chun Ma ◽

Xiang-mei Wen ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Indicator ◽

The Cancer Genome Atlas ◽

Related Gene ◽

Targeted Bisulfite Sequencing ◽

Specific Pcr ◽

Frequent Event ◽

Acute Myeloid

Abstract Background Obesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated. Results In the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML. Conclusions Our findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.

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Decitabine induces very early in vivo DNA methylation changes in blasts from patients with acute myeloid leukemia

Leukemia Research ◽

10.1016/j.leukres.2012.10.015 ◽

2013 ◽

Vol 37 (2) ◽

pp. 190-196 ◽

Cited By ~ 20

Author(s):

Rainer Claus ◽

Dietmar Pfeifer ◽

Maika Almstedt ◽

Manuela Zucknick ◽

Björn Hackanson ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Acute Myeloid

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Investigation of measurable residual disease in acute myeloid leukemia by DNA methylation patterns

Leukemia ◽

10.1038/s41375-021-01316-z ◽

2021 ◽

Author(s):

Tanja Božić ◽

Chao-Chung Kuo ◽

Jan Hapala ◽

Julia Franzen ◽

Monika Eipel ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Residual Disease ◽

Amplicon Sequencing ◽

Multiparametric Flow Cytometry ◽

Methylation Patterns ◽

Cg Dinucleotides ◽

Measurable Residual Disease ◽

Acute Myeloid

AbstractAssessment of measurable residual disease (MRD) upon treatment of acute myeloid leukemia (AML) remains challenging. It is usually addressed by highly sensitive PCR- or sequencing-based screening of specific mutations, or by multiparametric flow cytometry. However, not all patients have suitable mutations and heterogeneity of surface markers hampers standardization in clinical routine. In this study, we propose an alternative approach to estimate MRD based on AML-associated DNA methylation (DNAm) patterns. We identified four CG dinucleotides (CpGs) that commonly reveal aberrant DNAm in AML and their combination could reliably discern healthy and AML samples. Interestingly, bisulfite amplicon sequencing demonstrated that aberrant DNAm patterns were symmetric on both alleles, indicating that there is epigenetic crosstalk between homologous chromosomes. We trained shallow-learning and deep-learning algorithms to identify anomalous DNAm patterns. The method was then tested on follow-up samples with and without MRD. Notably, even samples that were classified as MRD negative often revealed higher anomaly ratios than healthy controls, which may reflect clonal hematopoiesis. Our results demonstrate that targeted DNAm analysis facilitates reliable discrimination of malignant and healthy samples. However, since healthy samples also comprise few abnormal-classified DNAm reads the approach does not yet reliably discriminate MRD positive and negative samples.

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