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The role of mutations in epigenetic regulators in myeloid malignancies
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The role of mutations in epigenetic regulators in myeloid malignancies
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Journal Article
The role of mutations in epigenetic regulators in myeloid malignancies
2012
Overview
Key Points
Mutations in epigenetic modifiers account for new classes of mutant disease alleles that contribute to the pathogenesis of myeloid malignancies in addition to the classical class I genes that affect proliferation and class II genes that affect differentiation.
Mutations in isocitrate dehydrogenase 1 (IDH1), IDH2 or tet methylcytosine dioxygenase 2 (
TET2
) affect 5-hydroxymethylcytosine modification of DNA, which alters methylation and haematopoietic development.
Mutations and translocations involving mixed-lineage leukaemia (
MLL
) as well as mutations in Polycomb repressive complex (PRC) components and interacting proteins affect histone modifications and can promote myeloid transformation.
Previously identified mutations, such as janus kinase 2 (
JAK2
)-V617F and fusion proteins involving translocation of the promyelocytic leukaemia (
PML
) gene, also contribute to epigenetic modifications in myeloid malignancies.
Epigenetic mutations are modifications that are reversible with therapy. Mutations in enzymatic modifiers represent attractive targets for directed therapy in myeloid malignancies.
Alterations to epigenetic regulators are a recently characterized class of oncogenic changes in myeloid malignancies. This Review discusses what these alterations mean for leukaemogenesis.
Recent genomic studies have identified novel recurrent somatic mutations in patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). In some cases these mutations occur in genes with known roles in regulating chromatin and/or methylation states in haematopoietic progenitors, and in other cases genetic and functional studies have elucidated a role for specific mutations in altering epigenetic patterning in myeloid malignancies. In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (
TET2
), isocitrate dehydrogenase 1 (
IDH1
),
IDH2
, additional sex combs-like 1 (
ASXL1
), enhancer of zeste homologue 2 (
EZH2
) and DNA methyltransferase 3A (
DNMT3A
), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights.
Publisher
Nature Publishing Group UK,Nature Publishing Group
