Role of DNA Methylation in the Pathogenesis and Treatment of Myelodysplastic Syndromes

Khan, Hina; Vale, Cristina; Bhagat, Tushar D.; Verma, Amit

doi:10.1053/j.seminhematol.2013.01.001

Cited by 43 publications

(30 citation statements)

References 118 publications

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“…Zebularine has been originally identified as a cytidine deaminase inhibitor (128, 141). Decitabine and 5-azacytidine are two well-known inhibitors of DNMTs that are effective against bone marrow disorders such as myelodysplastic syndrome (142). There are several DNMTs inhibitors that were studied in several cancers and these are summarized in Table 2.…”

Section: Breast Cancermentioning

confidence: 99%

DNA Methyltransferases: A Novel Target for Prevention and Therapy

et al. 2014

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Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents, and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2 or TRDMT1, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination, and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L, are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, it has been shown to function in self-renewal and maintenance of colon cancer stem cells and need to be studied in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anti-cancer targets. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represents a promising approach for the prevention and treatment of many cancers.

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Section: Breast Cancermentioning

confidence: 99%

DNA Methyltransferases: A Novel Target for Prevention and Therapy

et al. 2014

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“…23,24,[27][28][29][30] Several putative tumor suppressor genes have been shown to be hypermethylated in MDS, including cell cycle, signal transduction, lineage commitment, apoptosis, immune response and cytoskeletal remodeling genes, which may be then induced by AZA or DAC treatment. 29 In addition to 'absolute' methylation, also methylation density seems to play a significant role.…”

Section: Dna Methylationmentioning

confidence: 99%

Why methylation is not a marker predictive of response to hypomethylating agents

et al. 2014

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The azanucleotides azacitidine and decitabine have been shown to induce hematologic response and prolong survival in higher-risk myelodysplastic syndromes. They are inhibitors of DNA methyltransferase-1 and induce DNAhypomethylation. Induction of apoptosis is also clinically relevant, in particular during the first treatment cycles, when cytopenia is a frequent side-effect. Since the hypomethylating effect is reversible, and the malignant clone has been shown to persist in most responding patients, several cycles are necessary to achieve and maintain responses, while treatment interruption is associated with rapid relapse. Methylation studies have shown global and gene-specific hypermethylation in myelodysplastic syndromes, but there seems to be little relation between the degree of demethylation following hypomethylating treatment and hematologic response. The presence of concurrent genomic hypermethylation and hypomethylation may impair the predictive power of current detection techniques. This scenario has been complicated by the identification of epigenetic enzyme mutations, including TET2, IDH1/2, DNMT3A and EZH2, which are important for response to hypomethylating treatment. Changes in azanucleotide metabolism genes may also play a role. In the future, methylation analysis concentrating not only on promoters, but also on gene bodies and intergenic regions, may identify key genes in patients with the highest probability of response to azanucleotides and allow a patient-tailored approach. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nmore mutated clones during the course of the disease, which were not influenced by the type of treatment. Loss of response after stopping treatment is further favored by the fact that leukemic stem cells included in the Lin-CD34 + compartment seem to be spared from the activity of the drugs, probably also due to their non-proliferating status. In 15 MDS and AML patients achieving complete remission following AZA and valproic acid treatment, Craddock et al. showed that leukemic stem cells were substantially reduced, but were never eradicated, and expansion of this population took place before morphological relapse.14 Leukemic stem cells have been shown to overexpress multidrug resistance (MDR) transporters, including P-glycoprotein (P-gp). 15 Hypomethylating drugs have been shown to down-regulate P-gp expression in myeloid cell lines, with decitabine demethylating the repressor binding site of the MDR-1 gene. [16][17] Higher-risk MDS are characterized by a high degree of global methylation compared to normal CD34 + cells and de novo acute myeloid leukemia (AML). 18,19 In MDS, different methods have been used to study global methylation. Some of them, including liquid chromatography-mass spectroscopy/mass spectroscopy (LC-MS/MS), capture of methylated DNA by methyl-binding protein (MBD2), and the LINE-1 and the LUMA assays, evaluate genomic methylation without distinguishing regulatory from structural regions. After the seminal studies in which specific gene promoters we...

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“…The resulting DNA-protein cross-links trigger the proteosomal degradation machinery and lead to the depletion of the DNA methylation activities of the cell. Consequently, the replacement of deoxycytidine (dCyd) by aza-dCyd results in hypomethylation at the promoter DNA regions and the reactivation of epigenetically repressed genes (4). The transcriptional activation of tumor suppressor genes which are aberrantly silenced in cancer cells constitutes the basic principle of the epigenetic cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

Requena

Pérez-Moreno

Horváth

et al. 2016

Biochemical Journal

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Decitabine (5-aza-2′-deoxycytidine, aza-dCyd) is an anti-cancer drug used clinically for the treatment of myelodysplastic syndromes and acute myeloid leukaemia that can act as a DNA-demethylating or genotoxic agent in a dose-dependent manner. On the other hand, DCTPP1 (dCTP pyrophosphatase 1) and dUTPase are two ‘house-cleaning’ nucleotidohydrolases involved in the elimination of non-canonical nucleotides. In the present study, we show that exposure of HeLa cells to decitabine up-regulates the expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase, thus suggesting their contribution to the cellular response to this anti-cancer nucleoside. We present several lines of evidence supporting that, in addition to the formation of aza-dCTP (5-aza-2′-deoxycytidine-5′-triphosphate), an alternative cytotoxic mechanism for decitabine may involve the formation of aza-dUMP, a potential thymidylate synthase inhibitor. Indeed, dUTPase or DCTPP1 down-regulation enhanced the cytotoxic effect of decitabine producing an accumulation of nucleoside triphosphates containing uracil as well as uracil misincorporation and double-strand breaks in genomic DNA. Moreover, DCTPP1 hydrolyses the triphosphate form of decitabine with similar kinetic efficiency to its natural substrate dCTP and prevents decitabine-induced global DNA demethylation. The data suggest that the nucleotidohydrolases DCTPP1 and dUTPase are factors involved in the mode of action of decitabine with potential value as enzymatic targets to improve decitabine-based chemotherapy.

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Role of DNA Methylation in the Pathogenesis and Treatment of Myelodysplastic Syndromes

Cited by 43 publications

References 118 publications

DNA Methyltransferases: A Novel Target for Prevention and Therapy

DNA Methyltransferases: A Novel Target for Prevention and Therapy

Why methylation is not a marker predictive of response to hypomethylating agents

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

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