Abstract
Acute myeloid leukaemia (AML) is a haematological malignancy characterized by clonal stem cell proliferation and aberrant block in differentiation. Dysfunction of epigenetic modifiers contributes significantly to the pathogenesis of AML. One frequently mutated gene involved in epigenetic modification is DNMT3A (DNA methyltransferase-3-alpha), a DNA methyltransferase that alters gene expression by de novo methylation of cytosine bases at CpG dinucleotides. Approximately 22% of AML and 36% of cytogenetically normal AML cases carry DNMT3A mutations and around 60% of these mutations affect the R882 codon. These mutations have been associated with poor prognosis and adverse survival outcomes for AML patients. Advances in whole-exome sequencing techniques have recently identified a large number of DNMT3A mutations present in clonal cells in normal elderly individuals with no features of haematological malignancy. Categorically distinct from other preleukaemic conditions, this disorder has been termed clonal haematopoiesis of indeterminate potential (CHIP). Further insight into the mutational landscape of CHIP may illustrate the consequence of particular mutations found in DNMT3A and identify specific “founder” mutations responsible for clonal expansion that may contribute to leukaemogenesis. This review will focus on current research and understanding of DNMT3A mutations in both AML and CHIP.
Highlights
Acute myeloid leukaemia (AML) is a haematological malignancy characterized by clonal stem cell proliferation and aberrant block in differentiation
The presence of key mutations in preleukemic stem cells in MDS and AML, in addition to clonal haematopoiesis of indeterminate potential (CHIP), further supports the theory that such mutations in DNMT3A could be “founder” mutations, especially in the case of mutations found at the R882 codon hotspot
These mutations appear to arise in Haematopoietic stem cells (HSCs) and play a key role in the initiation of haematological malignancy
Summary
Histones such as H3K27me are observed to cover hypomethylated CpG canyons found in HSCs and are suggested to mark gene for methylation [24] Such canyon regions may potentiate the interaction between DNMT3A and histones for functional purposes as previously discussed with respect to PRC2 gene silencing. Several other epigenetic modifiers bind DNMT3A for functional purposes to modify gene expression One example of this is histone modifiers, such as H3K9 methyltransferase enzyme, which are observed to interact with DNMT3A [52], though the significance in respect to methylation activity is not well understood. Further studies may identify the significance and relevance of this interaction in human tissue
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