Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Azacytidine (5-aza-CR) and 5-aza-2'-deoxycytidine (5-aza-CdR), analogs of cytidine modified in position 5, were originally developed as antitumor agents, and have been useful in the treatment of both childhood and adult leukemias. These agents are cytotoxic per se, but also induce differentiation in several experimental systems, most notably the induction of muscle, adipocytes, and chondrocytes in cultures of drug-treated mouse embryo fibroblasts. The mechanisms underlying this drug-induced differentiation have been difficult to unravel, a fact which limits the rational design of differentiation therapy as a modulator of cancer using these agents. Induction of new developmental pathways in cultured cells involves stable, heritable changes, presumably of an epigenetic nature. Our early studies demonstrated that changes in methylation of cytosine in DNA occurred concurrently with changes in developmental potential, and that the presence of 5-azacytosine in DNA interfered with the action of DNA methyltransferase. Since DNA methylation is believed to be involved at some level in the regulation of gene expression, the hypothesis was developed that changes in methylation allowed the expression of new genes whose activity initiated new pathways of differentiation. The characterization of this drug-induced system of differentiation has therefore opened the way to identifying genes directly involved in the initiation or modification of pathways of differentiation. The first of these was MyoD, a member of a family of myogenic determination genes. Expression of MyoD in myogenic cell lines has been correlated with loss of methylation at specific sites in the genome, but the critical events leading to expression of MyoD and muscle differentiation are poorly understood. Recent developments in understanding this mechanism are discussed.
Leukemia 1993 May
PMID:5-Aza-2'-deoxycytidine: cell differentiation and DNA methylation. 768 53

DNA methylation changes are among the most common detectable abnormalities in human neoplasia. Hypermethylation within the promoters of selected genes appears to be especially common in all types of human hematopoietic neoplasms, and is usually associated with inactivation of the involved gene(s). Such hypermethylation-associated silencing of gene expression has been shown for several genes regulating the growth and differentiation of hematopoietic cells, including the estrogen receptor (ER) gene, P15, P16 and others. Hypermethylation within the promoters of some genes appear to be an early event in the pathogenesis of neoplasia (ER, P15), while other genes seem to become methylated during the progression of leukemias (HIC1, c-abl). The high prevalence of promoter methylation suggests that this molecular abnormality can be used to monitor disease activity during therapy. In addition, new technology allows the sensitive identification of gene hypermethylation in a background of normal cells, suggesting possible new strategies for the detection of minimal residual disease. Finally, reactivation of tumor-suppressor gene expression through pharmacologic inhibition of DNA methyltransferase and resultant DNA demethylation appears to be a promising new avenue of therapy in acute leukemia.
Leukemia 1997 Mar
PMID:DNA methylation changes in hematologic malignancies: biologic and clinical implications. 913 Jun 85

Aberrant DNA methylation has been observed consistently in many human tumours, in particular in the CpG islands of tumour suppressor genes, but the underlying mechanism of these changes remains unclear. To determine whether DNA methyltransferase expression is increased in leukaemia, we developed a standardised competitive RT-PCR assay to measure the level of DNA methyltransferase transcripts. Using this assay on bone marrow RNA samples from 12 patients with acute leukaemia, we observed a 4.4-fold mean increase in the level of DNA methyltransferase mRNA compared with normal bone marrow. These results support but do not prove the hypothesis that an increase in DNA methyltransferase activity is associated with malignant haematological diseases and may constitute a key step in carcinogenesis.
Leukemia 1998 Mar
PMID:Increased DNA methyltransferase expression in leukaemia. 952 24

Multidrug resistance (MDR) is a major problem in patients with hematological malignancies. Although drug-resistance is known to be induced by the expression of P-glycoprotein (P-gp) encoded by the MDR-1 gene, little is known about the mechanisms regulating this gene. Herein, we studied the DNA methylation patterns at the enhancer and repressor binding sites of the MDR-1 gene using the human erythroleukemia cell line K562 and its multidrug resistant derivative K562/ADM (adriamycin). Direct DNA sequence analysis demonstrated methylation to be present at the repressor site (minus 110 GC-box) of the MDR-1 gene in K562/ADM cells, but not in parental K562 cells. Methylation-specific PCR (MSP) analysis yielded similar results. Treatment of K562/ADM cells with 5-Aza-2'-deoxycytidine (decitabine; DAC), an inhibitor of DNA methyltransferase, caused demethylation of the repressor binding site of MDR-1 gene, as assessed by MSP, and also decreased P-gp expression, as assessed by flow cytometric and Northern blot analysis. Although it is generally accepted that DAC upregulates gene expression by demethylating the activator binding sites, our present results suggest that DAC induces down-regulation of P-gp expression as a result of demethylation at the repressor binding site in K562/ADM cells. In this regard, methylation-dependent regulation of the MDR-1 gene in K562/ADM cells is unique.
Leukemia 2000 Nov
PMID:Decitabine (5-Aza-2'-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells. 1106 27

In t(8;21) acute myeloid leukemia (AML), the AML1/ETO fusion protein promotes leukemogenesis by recruiting histone deacetylase (HDAC) and silencing AML1target genes important for hematopoietic differentiation. We hypothesized that depsipeptide (FR901228), a novel HDAC inhibitor evaluated in ongoing clinical trials, restores gene transcription and cell differentiation in AML1/ETO-positive cells. A dose-dependent increase in H3 and H4 histone acetylation was noted in depsipeptide-treated AML1/ETO-positive Kasumi-1 cells and blasts from a patient with t(8;21) AML. Consistent with this biological effect, we also showed a dose-dependent increase in cytotoxicity, expression of IL-3, here used as read-out for silenced AML1-target genes, upregulation of CD11b with other morphologic changes suggestive of partial cell differentiation in Kasumi-1 cells. Some of these biologic effects were also attained in other myeloid leukemia cell lines, suggesting that depsipeptide has differentiation and cytotoxic activity in AML cells, regardless of the underlying genomic abnormality. Notably, the activity of depsipeptide was enhanced by 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor (DNMT). These two agents in combination resulted in enhanced histone acetylation, IL-3 expression, and cytotoxicity, suggesting HDAC and DNMT activities as a potential dual target in future therapeutic strategies for AML1/ETO and other molecular subgroups of AML.
Leukemia 2003 Feb
PMID:Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells. 1259 35

The important cell cycle regulatory gene p15(INK4b) has been shown to be inactivated in acute myeloid leukemia and myelodysplastic syndrome. Little is known about the expression and epigenetic modification of this gene in chronic myelomonocytic leukemia (CMML) that belongs to the myelodysplastic/myeloproliferative disorders (MDS/MPD) with a high proportion of blastic transformation. Analysis of bone marrow trephines in a series of 33 CMML cases showed an aberrant p15(INK4b) gene methylation in up to 58% of cases. Methylation was analyzed employing different methylation-specific PCR and genomic sequencing protocols. It turned out to be spread over a broad area of the 5' region and exhibited substantial heterogeneity between cases and even in individual patients. The degree of aberrant methylation was correlated with a reduced mRNA as well as reduced protein expression, and was associated with a higher expression of DNA methyltransferase DNMT 3A. We conclude that aberrant gene methylation is a frequent event in CMML that might contribute to the pathogenesis of this MDS/MPD.
Leukemia 2003 May
PMID:Aberrant methylation and impaired expression of the p15(INK4b) cell cycle regulatory gene in chronic myelomonocytic leukemia (CMML). 1275 Jul 5

The class of DNA methyltransferase inhibitors is represented by azacitidine and decitabine. Azacitidine is approved for the treatment of patients in both low- and high-risk subtypes of myelodysplastic syndrome (MDS), and decitabine is currently under review by the FDA. Azacitidine phase III trial data, based upon the Cancer and Leukemia Group B (CALGB) study 9221, showed durable clinical and symptomatic improvement in bone marrow function, a reduction in the risk of leukemic transformation, and significant improvements in the quality of life of patients treated with azacitidine compared with supportive care alone. This study also provided data suggestive of improvement in survival in MDS patients. The experience with decitabine comprises a number of phase I/II studies and a phase III trial yet to be published. While there is a strong base of experience supporting the efficacy of DNA methyltransferase inhibitors in the treatment of MDS, a number of practical issues need to be explored further. These include the optimization of the timing and duration of treatment, and the prediction of response to therapy. Along with current experience, future studies will lead to the development of treatment algorithms, strategies for selecting patients (e.g. according to age, risk, classification, and cytogenetic profile), and the combination strategies, particularly with histone deacetylase inhibitors, in the management of MDS.
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PMID:Methylation inhibitor therapy in the treatment of myelodysplastic syndrome. 1634 Dec 36

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALK+ ALCL) is characterized by constitutive activation of the Janus kinase (JAK)3/signal transducers and activators of transcription 3 (STAT3) signaling pathway. SHP1, a tyrosine phosphatase that negatively regulates JAK/STAT, is frequently absent in ALK+ ALCL owing to gene methylation. To test the hypothesis that loss of SHP1 contributes to JAK3/STAT3 activation in ALK+ ALCL cells, we induced SHP1 expression using 5-aza-2'-deoxycytidine (5-AZA), an inhibitor of DNA methyltransferase, in ALK+ ALCL cell lines, and correlated with changes in the JAK3/STAT3 pathway. 5-AZA gradually restored SHP1 expression in Karpas 299 and SU-DHL-1 cells over 5 days. The initially low level of SHP1 expression did not result in significant changes to the expression or tyrosine phosphorylation of JAK3 and STAT3. However, higher levels of SHP1 seen subsequently correlated with substantial decreases in JAK3 and pJAK3, followed by pSTAT3 (but not STAT3). Importantly, the decrease in JAK3 was abrogated by MG132, a proteasome inhibitor. 5-AZA induced no significant increase in apoptosis but it sensitized ALCL cells to doxorubicin-induced apoptosis. Our findings support the concept that loss of SHP1 contributes to the constitutive activation of JAK3/STAT3 in ALK+ ALCL cells. SHP1 appears to downregulate JAK3 by two mechanisms: tyrosine dephosphorylation and increased degradation via the proteasome pathway.
Leukemia 2006 Sep
PMID:Restoration of shp1 expression by 5-AZA-2'-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma. 1687 Dec 83

Myelofibrosis (MF; primary or post-essential thrombocythemia/polycythemia vera) is incurable clonal myeloproliferative disorder, with no effective treatment. Epigenetic changes play an important role in cancer pathogenesis through transcriptional silencing of critical tumor suppressor genes. We conducted a phase-II study to evaluate the activity of DNA methyltransferase inhibitor, 5-azacitidine, in patients with MF. Thirty-four patients (76% previously treated) received 5-azacitidine at 75 mg/m(2) subcutaneously daily for 7 days, every 4 weeks. Twelve (35%) patients had abnormal cytogenetics and 19 (70%) of 27 evaluable patients had JAK2(V617F) mutation. Responses occurred in 8 (24%) patients after a median of 5 months (range, 3-10). Partial response occurred in 1 (3%) patient (duration 22+ months) and clinical improvement in 7 (21%) patients (median duration 4 months; range, 2-8.5). Myelosuppression was the major adverse effect, with grade 3-4 neutropenia in 10 (29%) patients. Global DNA methylation assessed by the long interspersed nucleotide element (LINE) bisulfite/pyrosequencing assay decreased from 53% pretherapy to 44% on day 14 (P=0.0014) and returned to 50% at the end of the first 28-day cycle (P=0.016). 5-azacitidine is relatively well tolerated and results in induction of global hypomethylation in patients with MF, but results in limited clinical activity.
Leukemia 2008 May
PMID:A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis. 1850 50

The three DNA methyltransferase (DNMT)-inhibiting cytosine nucleoside analogues, azacitidine, decitabine and zebularine, which are currently studied as nonintensive therapy for myelodysplastic syndromes and acute myeloid leukemia (AML), differ in structure and metabolism, suggesting that they may have differential molecular activity. We investigated cellular and molecular effects of the three substances relative to cytarabine in Kasumi-1 AML blasts. Under in vitro conditions mimicking those used in clinical trials, the DNMT inhibitors inhibited proliferation and triggered apoptosis but did not induce myeloid differentiation. The DNMT inhibitors showed no interference with cell-cycle progression whereas cytarabine treatment resulted in an S-phase arrest. Quantitative methylation analysis of hypermethylated gene promoters and of genome-wide LINE1 fragments using bisulfite sequencing and MassARRAY suggested that the hypomethylating potency of decitabine was stronger than that of azacitidine; zebularine showed no hypomethylating activity. In a comparative gene expression analysis, we found that the effects of each DNMT inhibitor on gene transcription were surprisingly different, involving several genes relevant to leukemogenesis. In addition, the gene methylation and expression analyses suggested that the effects of DNMT-inhibiting cytosine nucleoside analogues on the cellular transcriptome may, in part, be unrelated to direct promoter DNA hypomethylation, as previously shown by others.
Leukemia 2009 Jun
PMID:The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. 1919 70


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