Review Article | Published:

The role of mutations in epigenetic regulators in myeloid malignancies

Nature Reviews Cancer volume 12, pages 599612 (2012) | Download Citation

Abstract

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.

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.

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Acknowledgements

This work was supported in part by National Institutes of Health grants U54CA143798-01 (Physical Sciences Oncology Center) and 1R01CA138234-01 to R.L.L., and by grants from the Starr Cancer Consortium and from Gabrielle's Angel Foundation to R.L.L. O.A.-W. is a Basic Research Fellow of the American Society of Hematology. A.H.S. is a Dana Fellow in Biomedical Research. R.L.L. is a Scholar of the Leukemia and Lymphoma Society.

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    • Alan H. Shih
    •  & Omar Abdel-Wahab

    These authors contributed equally to this work

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  1. Human Oncology and Pathogenesis Program.

    • Alan H. Shih
    • , Omar Abdel-Wahab
    • , Jay P. Patel
    •  & Ross L. Levine
  2. Leukemia Service, Department of Medicine. Memorial Sloan–Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA.

    • Alan H. Shih
    • , Omar Abdel-Wahab
    •  & Ross L. Levine

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Correspondence to Ross L. Levine.

Glossary

Myeloproliferative neoplasms

(MPNs). Clonal disorders of haematopoiesis that are characterized by terminal myeloid cell expansion. Classic MPNs include polycythemia vera (PV), essential thrombocythemia (ET), chronic myeloid leukaemia (CML), primary myelofibrosis (PMF), chronic neutrophilic leukaemia, chronic eosinophilic leukaemia and mast cell disease.

Myelodysplastic syndrome

(MDS). A heterogeneous group of malignant haematopoietic disorders that are characterized by dysplastic and ineffective blood cell production and a variable risk of transformation to acute leukaemia. MDS may occur de novo or arise years after exposure to mutagens (including radiation and some types of chemotherapy).

Acute myeloid leukaemia

(AML). A group of clonal myeloid disorders that involve precursor cells with a reduced capacity to differentiate into more mature cellular elements and with increased proliferation and self-renewal.

Myelopoiesis

The process of haematopoietic differentiation from haematopoietic stem cells to mature granulocytes, monocytes, erythroid cells and megakaryocytes.

Long-term haematopoietic stem cell

(LT-HSC). The population of HSCs that is capable of both self-renewal and the production of short-term haematopoietic stem or progenitor cells.

Chronic myelomonocytic leukaemia

(CMML). A clonal disorder of haematopoiesis that is characterized by the expansion of monocytes within the bone marrow and/or peripheral blood, as well as dysplasia of myeloid-precursor cellular elements.

Base-excision repair

(BER). A mechanism that repairs damaged DNA throughout the cell cycle. It is responsible for removing small, non-helix-distorting base lesions from the genome. BER is initiated by DNA glycosylases, which recognize and remove specific inappropriate bases, forming an abasic site. These are then cleaved by an endonuclease, and the resulting single-strand break can then be processed by either short-patch BER (through which a single nucleotide is replaced) or long-patch BER (through which 2–10 new nucleotides are synthesized).

HpaII tiny fragment enrichment by ligation-mediated PCR assay

(HELP assay). A technique that is used for determining the extent and pattern of DNA methylation within and around individual genes or an entire genome. Representations generated by HpaII and by MspI restriction enzyme digestion of the genome followed by ligation-mediated PCR are compared to generate maps of methylation abundance and distribution. HpaII digests 5′-CCGG-3′ sites when the cytosine in the central CpG dinucleotide is unmethylated, whereas MspI digests methylated and unmethylated DNA at those sites.

Krebs cycle

Also known as the citric acid cycle or the tricarboxylic acid cycle. The Krebs cycle is a series of chemical reactions that is used by all aerobic organisms to generate NADH and certain amino acids through the oxidation of acetate.

Peroxisomes

Organelles that are found in virtually all eukaryotic cells. They are involved in the catabolism of very-long-chain fatty acids, branched-chain fatty acids, D-amino acids, polyamines and the biosynthesis of plasmalogens and etherphospholipids.

International Prognostic Scoring System

A risk-assessment system to evaluate the prognosis of newly diagnosed patients with myelodysplastic syndrome (MDS). This uses bone marrow blast percentage, karyotype and the number of cytopenias to determine a risk score that is then used to predict median survival and time to transformation to acute myeloid leukaemia (AML).

Trithorax

A group of proteins that function in histone-modifiying complexes to activate gene expression by inducing trimethylation of lysine 4 of histone H3 (H3K4me3) at specific sites in chromatin that are recognized by the complex.

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