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: 29.54). 08/2012; 12(9):599-612. DOI: 10.1038/nrc3343
Source: PubMed

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.

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    • "Detection of more than one TET2 mutation in individual patients suggests the presence of multiple leukaemic clones. The mutation frequency of TET2 in our small cohort is much higher than previously reported (Shih et al, 2012). This could be due to the small sample size and the selection of myeloproliferative variant of CMML (indicated by high white blood cell and monocyte counts) and transformed AML in our study. "
    British Journal of Haematology 04/2014; 166(3). DOI:10.1111/bjh.12871 · 4.96 Impact Factor
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    • "These findings suggest that the loss-of-function mutations in EZH2 may contribute to myeloid neoplasm [6] [76] [77]. The oncogenic implications of both loss and gain of function of EZH2 implies dual, tissue-specific roles as both oncogene and tumor suppressor [6] [8] [77]. Mutations in EED and SUZ12 rarely occur in patients with MDS/MPN overlap disorders or PMF but may occur in conjunction with EZH2 [76]. "
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    ABSTRACT: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated.
    Advances in Hematology 03/2014; 2014(8):103175. DOI:10.1155/2014/103175
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    • "5hmC levels have been analyzed in different tissues, and high levels of this modification were found in brain, kidney, or liver [9] [10] [12]. Loss of 5hmC has been observed in different cancers [13] and linked to decreased TET expression and mutations in isocitrate dehydrogenase 1 (IDH1 and IDH2) [14]. In mouse embryonic stem cells, 5hmC was found to be associated with active promoters and correlated with increased expression, and silencing of TET1 and TET2 resulted in increased 5mC and decreased expression of a group of genes including pluripotency factors [15]. "
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    ABSTRACT: Change of DNA cytosine methylation (5mC) is an early event in the development of cancer, and the recent discovery of a 5-hydroxymethylated form (5hmC) of cytosine suggests a regulatory epigenetic role that might be different from 5-methylcytosine. Here, we aimed at elucidating the role of 5hmC in breast cancer. To interrogate the 5hmC levels of the leucine zipper, putative tumor suppressor 1 (LZTS1) gene in detail, we analyzed 75 primary breast cancer tissue samples from initial diagnosis and 12 normal breast tissue samples derived from healthy persons. Samples were subjected to 5hmC glucosyltransferase treatment followed by restriction digestion and segment-specific amplification of 11 polymerase chain reaction products. Nine of the 11 5'LZTS1 fragments showed significantly lower (fold change of 1.61-6.01, P < .05) 5hmC content in primary breast cancer tissue compared to normal breast tissue samples. No significant differences were observed for 5mC DNA methylation. Furthermore, both LZTS1 and TET1 mRNA expressions were significantly reduced in tumor samples (n = 75, P < .001, Student's t test), which correlated significantly with 5hmC levels in samples. 5hmC levels in breast cancer tissues were associated with unfavorable histopathologic parameters such as lymph node involvement (P < .05, Student's t test). A decrease of 5hmC levels of LZTS1, a classic tumor suppressor gene known to influence metastasis in breast cancer progression, is correlated to down-regulation of LZTS1 mRNA expression in breast cancer and might epigenetically enhance carcinogenesis. The study provides support for the novel hypothesis that suggests a strong influence of 5hmC on mRNA expression. Finally, one may also consider 5hmC as a new biomarker.
    Translational oncology 12/2013; 6(6):715-21. DOI:10.1593/tlo.13523 · 3.40 Impact Factor
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