The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer

Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA.
Nature Reviews Cancer (Impact Factor: 37.4). 08/2012; 12(9):599-612. DOI: 10.1038/nrc3343
Source: PubMed


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.

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    • "in patients suffering from a wide variety of hematopoietic diseases (for review, see Solary et al. 2014), including malignancies such as myelodysplastic syndrome (MDS) (Delhommeau et al. 2009; Langemeijer et al. 2009; Messerschmidt et al. 2014), chronic myelomonocytic leukemia (CMML) (Kosmider et al. 2009; Baylin and Jones 2011), acute myeloid leukemia (AML) (Baylin and Jones 2011; Weissmann et al. 2012), and B-and T-cell lymphomas (Quivoron et al. 2011; Asmar et al. 2013; Teschendorff et al. 2013; Issa 2014; Schoofs et al. 2014). Genetic inactivation of Tet2 in the mouse hematopoietic system confers a competitive advantage to stem and progenitor cells and disrupts terminal differentiation, resulting in a CMML-like phenotype (Li et al. 2011; Moran-Crusio et al. 2011; Quivoron et al. 2011; Shide et al. 2012; Shih et al. 2012). Although this leads to increased susceptibility to cellular transformation, the resulting hematopoietic malignancies occur with low penetrance. "
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    ABSTRACT: DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles and hallmarks of human AML1-ETO-induced AML. Using this model, we show that the primary effect of Tet2 loss in preleukemic hematopoietic cells is progressive and widespread DNA hypermethylation affecting up to 25% of active enhancer elements. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner but increases relative to population doublings. We confirmed this specific enhancer hypermethylation phenotype in human AML patients with TET2 mutations. Analysis of immediate gene expression changes reveals rapid deregulation of a large number of genes implicated in tumorigenesis, including many down-regulated tumor suppressor genes. Hence, we propose that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation and that it is the combined silencing of several tumor suppressor genes in TET2 mutated hematopoietic cells that contributes to increased stem cell proliferation and leukemogenesis. © 2015 Rasmussen et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 04/2015; 29(9). DOI:10.1101/gad.260174.115 · 10.80 Impact Factor
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    • "Both the genes play a critical role in the citric acid cycle IDH1 in the cytoplasm and peroxisome and IDH2 in the mitochondria. Both IDH1 and IDH2 promote the conversion of isocitrate to α-ketoglutarate (α-KG) that is associated with the reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to NADPH [8,11,20]. Mutations in IDH1 and IDH2 are heterozygous and occur in highly conserved arginine residues (IDH1 R132 and IDH2 R140/R172). Mutations at IDH2 R140 always result in the conversion of arginine to glutamine, whereas substitutions at IDH1 R132 and IDH2 R172 result in a wide range of amino acid replacements [12]. "
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    ABSTRACT: Background Mutations in epigenetic modifiers were reported in patients with acute myeloid leukaemia (AML) including mutations in DNA methyltransferase 3A gene (DNMT3A) in 20%-30% patients and mutations in isocitrate dehydrogenase 1/2 gene (IDH1/2) in 5%-15% patients. Novel studies have shown that mutations in DNMT3A and IDH1/2 influence prognosis, indicating an increasing need to detect these mutations during routine laboratory analysis. DNA sequencing for the identification of these mutations is time-consuming and cost-intensive. This study aimed to establish rapid screening tests to identify mutations in DNMT3A and IDH1/2 that could be applied in routine laboratory procedures and that could influence initial patient management. Methods In this study we developed an endonuclease restriction method to identify the most common DNMT3A mutation (R882H) and an amplification-refractory mutation system (ARMS) to analyse IDH2 R140Q mutations. Furthermore, we compared these methods with HRM analysis and evaluated the latter for the detection of IDH1 mutations. Results Of 230 samples from patients with AML 30 (13%) samples had DNMT3A mutations, 16 (7%) samples had IDH2 R140Q mutations and 36 (16%) samples had IDH1 mutations. Sensitivity assays performed using serial dilutions of mutated DNA showed that ARMS analysis had a sensitivity of 4.5%, endonuclease restriction had a sensitivity of 0.05% and HRM analysis had a sensitivity of 5.9%–7.8% for detecting different mutations. HRM analysis was the best screening method to determine the heterogeneity of IDH1 mutations. Furthermore, for the identification of mutations in IDH2 and DNMT3A, endonuclease restriction and ARMS methods showed a perfect concordance (100%) with Sanger sequencing while HRM analysis showed a near-perfect concordance (approximately 98%). Conclusion Our study suggested that all the developed methods were rapid, specific and easy to use and interpret. HRM analysis is the most timesaving and cost-efficient method to rapidly screen all the 3 genes at diagnosis in samples obtained from patients with AML. Endonuclease restriction and ARMS assays can be used separately or in combination with HRM analysis to obtain more reliable results. We propose that early screening of mutations in patients with AML having normal karyotype could facilitate risk stratification and improve treatment options.
    Journal of Experimental & Clinical Cancer Research 05/2014; 33(1):44. DOI:10.1186/1756-9966-33-44 · 4.43 Impact Factor
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    • "Based on SNP array analysis [4] [55] and NGS studies [3] [56], novel biomarkers have been discovered that include mutations in transcription factors (WT1, RUNX1, and GATA2), in genes influencing transcriptional regulation (NRAS, KRAS, CBL, KIT, and RAD21), and in epigenetic modifiers (TET2, IDH1, IDH2, DNMT3A, ASXL1, MLL, TET1, BCOR, NSD1, PHF6, DNMT1, NSD1, EZH2, and MLL3) [1] [33] [57]. Most of these "
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    ABSTRACT: The development of single nucleotide polymorphism (SNP) microarray analysis and next generation sequencing (NGS) has significantly contributed to comprehensively characterize the genetic changes underlying acute myeloid leukemia (AML). These genomics technologies have led to the identification of an increasing number of genomic aberrations and gene mutations that cause epigenetic changes and lead to deregulated gene expression. In accordance, AML patients present with a distinct and almost individual combination of somatically acquired genetic alterations reflecting the molecular heterogeneity of the disease. Some of these are known driver mutations perturbing self-renewal, proliferation, and hematopoietic differentiation, whereas many mutations also represent mere passenger events, which do not significantly contribute to AML. In the future, we will have to discriminate driver from passenger mutations and in addition it will be crucial to evaluate the prognostic and predictive values of the respective driver mutations, especially in the context of the overall genetic background. While first genetic markers have already been translated into the daily clinical routine by impacting treatment decisions, novel biomarkers are needed especially to improve the effectiveness of molecular targeted therapies, which have to be put into the perspective of mutational networks to further “precision medicine” by personalized combination treatment approaches.
    Acta haematologica Polonica 05/2014; 45(4). DOI:10.1016/j.achaem.2014.05.001
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