Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2

By M. Ko, Yun Huang, A. Jankowska, U. J. Pape, Mamta Tahiliani, Hozefa S. Bandukwala, Jungeun An, E. Lamperti, Kian Peng Koh, Rebecca D. Ganetzky and 5 more. Nature, 2010

1,313 citations recorded by the source corpus.

TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs.

Subfields: Genetics, Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/301cda61c3ae3bdc6939719d9554c03b2c5c343a

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In Genetics

1. Yi Zhang
2. Hao Wu
3. G. Semenza
4. Manel Esteller
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In Hematology

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2. Yi Zhang
3. T. Suda
4. Hao Wu
5. Peter A. Jones
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In Molecular Biology

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2. Yi Zhang
3. Peter A. Jones
4. Manel Esteller
5. M. V. Vander Heiden
6. Wolf Reik
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8. G. Semenza

Citations in the corpus

• Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011, neutral): “Within the TET family of proteins, TET1, TET2, and TET3 have been shown to modify DNA by hydroxylating 5-methylcyto- sine (5mC) (Ko et al., 2010; Tahiliani et al., 2009), and the TET2 mutant proteins observed in these patients with myeloid malig- nancies have been shown to be deficient in this…”
• Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. (2013, neutral): “Mutations in the IDH2 and TET2 genes were also linked to lower genomic hmC levels and altered gene expression patterns in myeloid cancers (Ko et al., 2010; Konstandin et al., 2011).”
• Cancer epigenetics reaches mainstream oncology (2011, background): “, and homozygous null mutations and chromosomal deletions involving the TET2 locus have been described in various myeloid malignancie”
• CpG islands and the regulation of transcription. (2011, neutral): “Indeed, mutations in the TET2 gene are frequent in leukemias and compromise the hydroxylation reaction (Ko et al. 2010).”
• Metabolic regulation of hematopoietic stem cells in the hypoxic niche. (2011, background): “TET2 encodes an O2-binding, 2-OG-dependent enzyme that catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, leading the subsequent DNA demethylation (Ko et al., 2010).”
• Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome (2012, neutral): “The TET proteins, which are responsible for conversion of 5mC to 5hmC, have been shown to function in ESC regulation, myelopoiesis and zygote development (Dawlaty et al., 2011; Gu et al., 2011; Iqbal et al., 2011; Ito et al., 2010; Ko et al., 2010; Koh et al., 2011; Wossidlo et al., 2011).”
• TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. (2011, neutral): “We and others have recently identified mutations in the TET2 gene that frequently represent an early event during the development of a wide variety of human myeloid malignancies, including myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF)”
• Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, methodology): “The approaches include shRNA-based Tet2 knockdown and targeted deletion of Tet2 in mice (Figueroa et al. 2010; Ko et al. 2010, 2011; Li et al. 2011; MoranCrusio et al. 2011; Quivoron et al. 2011).”
• The role of mutations in epigenetic regulators in myeloid malignancies (2012, methodology): “Genome-wide DNA methylation studies in MDS and AML have reported both hypermethylated and hypomethylated profiles associated with TET2-mutant disease (48, 50, 51).”