Abstract
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.
Highlights
Definitive hematopoiesis refers to the hierarchical process in which hematopoietic stem cells (HSCs) undergo differentiation and give rise to all various lineages of mature hematopoietic cells
DNA methylation is catalyzed by three conserved DNA methyltransferases (DNMTs), which include the de novo DNMT3A and DNMT3B, and the maintenance DNMT1
60% of DNMT3A mutations in Acute myeloid leukemia (AML) patients occur at the residue R882, which is located at the methyltransferase catalytic domain [26,54,55]
Summary
Definitive hematopoiesis refers to the hierarchical process in which hematopoietic stem cells (HSCs) undergo differentiation and give rise to all various lineages of mature hematopoietic cells. Hematopoiesis is a complicated process including HSC specification, expansion, and differentiation. It requires precise orchestration of the transcriptional regulation and signal transduction within the cells and with the bone marrow niche [1,2,3]. DNA methylation denotes the addition of methyl group to the fifth carbon position of cytosine, which is frequently occurring at CpG dinucleotides. It is involved in various cellular processes, in genomic imprinting, X-chromosome inactivation, repression of transposable elements, and regulation of gene expression [6,7]. We focus on the current knowledge of DNA methylation in AML and evaluate its clinical implications in AML diagnosis and prognosis
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