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Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute Myeloid Leukaemia and Clonal Haematopoiesis.

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.
PMID
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Authors

Mayor MeshTerms

DNA (Cytosine-5-)-Methyltransferase

Epigenesis, Genetic

Gene Expression Regulation, Enzymologic

Gene Expression Regulation, Leukemic

Leukemia, Myeloid, Acute

Mutation, Missense

Neoplasm Proteins

Keywords
Journal Title biomed research international
Publication Year Start




PMID- 28286768
OWN - NLM
STAT- MEDLINE
DA  - 20170313
DCOM- 20170317
LR  - 20170317
IS  - 2314-6141 (Electronic)
VI  - 2017
DP  - 2017
TI  - Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute
      Myeloid Leukaemia and Clonal Haematopoiesis.
PG  - 5473197
LID - 10.1155/2017/5473197 [doi]
AB  - 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.
FAU - Chaudry, Sabah F
AU  - Chaudry SF
AD  - Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex
      BN1 9PS, UK.
FAU - Chevassut, Timothy J T
AU  - Chevassut TJ
AUID- ORCID: 0000-0001-8672-1906
AD  - Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex
      BN1 9PS, UK.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20170214
PL  - United States
TA  - Biomed Res Int
JT  - BioMed research international
JID - 101600173
RN  - 0 (Neoplasm Proteins)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase)
RN  - EC 2.1.1.37 (DNA methyltransferase 3A)
SB  - IM
MH  - Amino Acid Substitution
MH  - Animals
MH  - *DNA (Cytosine-5-)-Methyltransferase/biosynthesis/genetics
MH  - *Epigenesis, Genetic
MH  - *Gene Expression Regulation, Enzymologic
MH  - *Gene Expression Regulation, Leukemic
MH  - Hematopoiesis/genetics
MH  - Humans
MH  - *Leukemia, Myeloid, Acute/epidemiology/genetics
MH  - *Mutation, Missense
MH  - *Neoplasm Proteins/biosynthesis/genetics
PMC - PMC5329657
COI - The authors declare that there is no conflict of interests.
EDAT- 2017/03/14 06:00
MHDA- 2017/03/18 06:00
CRDT- 2017/03/14 06:00
PHST- 2016/07/28 [received]
PHST- 2016/10/18 [revised]
PHST- 2016/11/14 [accepted]
AID - 10.1155/2017/5473197 [doi]
PST - ppublish
SO  - Biomed Res Int. 2017;2017:5473197. doi: 10.1155/2017/5473197. Epub 2017 Feb 14.

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