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

724 STAT3 inhibition in acute myeloid leukemia cells allows for TLR9-driven differentiation to immunogenic monocytic cells and induction of T-cell mediated immune responses

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A767-A767
Author(s):  
Yu-Lin Su ◽  
Marcin Kortylewski ◽  
Priyanka Duttagupta
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Immune Responses ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Dna Methyltransferases ◽  
Leukemic Cells ◽  
Stat3 Inhibition ◽  
Acute Myeloid

BackgroundSignal transducer and activator of transcription factor 3 (STAT3) is commonly activated in acute myeloid leukemia (AML) and known for supporting cancer cell proliferation and survival. Recently, we demonstrated that STAT3 also plays a critical role ensuring AML immune evasion. Intravenous injections of bi-functional decoy oligodeoxyribonucleotides (CpG-STAT3dODN) blocked STAT3 activity and induced TLR9 signaling in Cbfb/MYH11/Mpl (CMM) AML cells, thereby resulting in immunogenic effects and T cell-mediated immune responses and leukemia regression.MethodsTo understand the molecular mechanisms of the CpG-STAT3 decoy-induced AML differentiation and immunogenicity, we performed global gene expression analysis on the in vivo treated AML cells using oligonucleotide strategy as well as an inducible STAT3 gene silencing.ResultsTranscriptional profiling revealed the upregulation of myeloid cell differentiation related genes, such as Irf8, Cebpa, and Gadd45A with reduction of oncogenic Runx1 and Run1t1 in CMM leukemic cells after CpG-STAT3dODN but not after control treatments. CpG-STAT3dODN treatment also upregulated set of antigen-presentation related genes, such as CIIta, Il12a, and Ifng in CMM AML cells. Importantly, the induction of Irf8 and Cebpa, with the concomitant suppression of Runx1 were found specifically in the subset of differentiated CD11b+ CMM cells but not in the bulk CD11b– leukemic cells. These effects were likely related to epigenetic reprogramming of AML cells as indicated by treatment-induced changes in the expression and protein levels of STAT3 regulated DNA methyltransferases, DNMT1 and DNMT3a/b. Furthermore, our initial studies suggest that STAT3 inhibition/TLR9 activation leads to immunogenic effects also in a xenotransplanted model of human FLT3-ITD MV4-11 leukemia in humanized mice. CpG-STAT3dODN alone or together with clinically-relevant demethylating agent (Decitabine) triggered differentiation of MV4-11 cells into CD11b+HLA-DR+CD86+ antigen-presenting cells (APCs) and increased ratio of CD8+ to regulatory T cells in the bone marrow, thereby reducing leukemia burden.ConclusionsOur results suggest that eliminating STAT3 permits the TLR9-driven reprogramming of AML cells into APCs to unleash T cell-mediated responses against leukemia.

Sign in / Sign up

Export Citation Format

Share Document