Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.37 (DNA methyltransferase)
4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelodysplastic syndromes (MDS) are a heterogenous group of hematopoietic stem cell disorders that are multifactorial in their etiology. Aberrant DNA hypermethylation is now thought to be involved in MDS, as numerous tumor-suppressor genes have been identified that are silenced in these patients. Thus, the use of DNA methyltransferase inhibitors, such as 5-aza-2'-deoxycytidine (decitabine, Dacogen, MGI Pharma Inc, Bloomington, MN), for reversal of this process appears to be a rational intervention that may influence the course of the disease. Several phase I/II studies have been conducted using a low-dose schedule of decitabine in MDS patients. Based on these studies, decitabine appears to be effective and generally well tolerated, especially in those patients with worse prognostic indicators. Recent results of a phase III study also confirmed that patients treated with decitabine compared to standard supportive care had higher overall response rates and longer time to AML transformation. Decitabine appears to be a promising new therapy for the treatment of MDS; however, defining the optimal dosing schedule and exploring the possible use in combination with other agents such as the histone deacetylase inhibitors need further evaluation.
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PMID:Decitabine in myelodysplastic syndromes. 1601 1

Therapeutic options for patients with relapse of MDS or high risk AML after allogeneic stem cell transplantation are limited. We here present the case of a 64-year-old female patient with MDS, who received peripheral blood stem cells from her HLA-identical brother after a non-myeloablative conditioning regimen. Two months after allogeneic transplantation she suffered from a relapse, now fulfilling WHO criteria for AML with a bone marrow blast count of 91%. We then decided to treat her with azacitidine, a DNA methyltransferase inhibitor with proven antileukemic activity. The patient achieved a complete haematological response after two cycles and full donor chimerism after a single dose of donor lymphocytes. We postulate that azacitidine acts through a direct reduction of malignant cells and may in addition augment the immunologic effects of donor lymphocyte infusions.
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PMID:Successful treatment of relapsed AML after allogeneic stem cell transplantation with azacitidine. 1662 Sep 71

The acute promyelocytic leukemia-specific PML-RARalpha fusion protein is a dominant-negative transcriptional repressor of retinoic acid receptor (RAR) target genes, which recruits HDAC and corepressor proteins and inhibits coactivators. Another oncogenic transcription factor, AML1-ETO, was proposed to cause an HDAC-dependent repression of RAR target genes. The RAR target RARbeta2 gene has been reported to be frequently silenced by hypermethylation in many types of cancer cells. We examined the methylation status of the RARbeta2 and asked if demethylation could reverse ATRA resistance in ATRA-resistant PML-RARalpha and AML1-ETO-positive cells. PML-RARalpha positive NB4 and its ATRA-resistant subvariant MR2 and AML1-ETO expressing Kasumi-1 cells had heterozygous methylation of RARbeta2. Although DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine partially reversed RARbeta2 CpG methylation in these cells, it did not significantly enhance ATRA-induced RARbeta2 mRNA expression and induction of maturation. However, the histone acetylase inhibitor SAHA combined with ATRA significantly reactivated RARbeta2 mRNA both in NB4 and MR2 cells with degradation of PML-RARalpha, which was associated with maturation. In contrast, SAHA did not affect AML1-ETO levels and failed to induce RARbeta2 expression and maturation in Kasumi-1 cells. In primary AML samples, RARbeta2 expression was uniformly low; however, no specific correlation was observed between the methylation of the RARbeta2 gene and expression of the fusion proteins, PML-RARalpha, and AML1-ETO. These results demonstrate that oncogenic PML-RARalpha and AML1-ETO translocations are rarely associated with RARbeta2 promoter methylation in primary AML samples.
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PMID:PML-RARalpha and AML1-ETO translocations are rarely associated with methylation of the RARbeta2 promoter. 1683 76

In vitro and in vivo, myeloid leukemic and preleukemic cells exhibit variable sensitivity to the antiproliferative and proapoptotic effects induced already at low concentrations of DNA methyltransferase (DNMT) inhibitors. The molecular mechanisms underlying this variable sensitivity of leukemic blasts to azanucleosides such as 5-azacytidine and 5-aza-2'-deoxycytidine (DAC) may involve modifier effects of specific fusion proteins such as AML1/ETO. The cyclin-dependent kinase inhibitor p15/INK4b is one potential target of DNA demethylating activity in AML and MDS where it is frequently silenced by hypermethylation. To study sensitivity to DAC in myeloid leukemia cells, we chose the myeloid cell lines Kasumi-1 (expressing AML1/ETO), KG-1 and KG-1a (both AML1/ETO-negative) all of which a highly methylated p15/INK4b gene. Treatment with DAC resulted in dose-dependent regional demethylation of p15/INK4b in Kasumi-1 and KG-1, but only to a modest degree in KG-1a cells. Demethylation was associated with induction of p15/INK4b protein expression. Growth-inhibitory and proapoptotic activity of DAC was significantly higher in Kasumi-1 than in KG-1a cells, and sensitization of cells to a cooperating effect of All-trans retinoic acid and of the histone deacetylase (HDAC) inhibitor Trichostatin A was observed. DAC-induced growth inhibition and apoptosis were enhanced when AML1/ETO was conditionally expressed in AML1/ETO-negative U-937 cells. In conclusion, hypomethylation and reactivation of p15/INK4b in myeloid cell lines are among the molecular events associated with DAC-induced growth arrest and apoptosis. Further studies of AML1/ETO as a modifier of the epigenotype and sensitivity of myeloid cells to inhibitors of DNMTs and HDACs appear warranted.
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PMID:Reversal of p15/INK4b hypermethylation in AML1/ETO-positive and -negative myeloid leukemia cell lines. 1705 12

Epigenetic modifiers are currently in clinical use for various tumor types. Recently, numerous studies supporting the combination of histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors have emerged, encouraging early clinical trials of these agents together. Here we show that MS-275, an HDACi, and 5-azacytidine, a methyltransferase inhibitor, display synergistic cytotoxicity and apoptosis in AML and ALL cells. Intracellular production of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, is a novel marker for this synergism in ALL cells. These data suggest that assessment of oxidative stress can serve as a marker of the concerted action of MS-275 and 5-azacytidine.
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PMID:Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells. 1803 11

The PRC2 complex protein EZH2 is a histone methyltransferase that is known to bind and recruit DNMT1 to the DNA to modulate DNA methylation. Here, we determined that the pan-HDAC inhibitor panobinostat (LBH589) treatment depletes DNMT1 and EZH2 protein levels, disrupts the interaction of DNMT1 with EZH2, as well as de-represses JunB in human acute leukemia cells. Similar to treatment with the hsp90 inhibitor 17-DMAG, treatment with panobinostat also inhibited the chaperone association of heat shock protein 90 with DNMT1 and EZH2, which promoted the proteasomal degradation of DNMT1 and EZH2. Unlike treatment with the DNA methyltransferase inhibitor decitabine, which demethylates JunB promoter DNA, panobinostat treatment mediated chromatin alterations in the JunB promoter. Combined treatment with panobinostat and decitabine caused greater attenuation of DNMT1 and EZH2 levels than either agent alone, which was accompanied by more JunB de-repression and loss of clonogenic survival of K562 cells. Co-treatment with panobinostat and decitabine also caused more loss of viability of primary AML but not normal CD34(+) bone marrow progenitor cells. Collectively, these findings indicate that co-treatment with panobinostat and decitabine targets multiple epigenetic mechanisms to de-repress JunB and exerts antileukemia activity against human acute myeloid leukemia cells.
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PMID:Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. 1927 3

Abnormal epigenetic regulation has been implicated in oncogenesis. We report here the identification of somatic mutations by exome sequencing in acute monocytic leukemia, the M5 subtype of acute myeloid leukemia (AML-M5). We discovered mutations in DNMT3A (encoding DNA methyltransferase 3A) in 23 of 112 (20.5%) cases. The DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. Notably, there were alterations of DNA methylation patterns and/or gene expression profiles (such as HOXB genes) in samples with DNMT3A mutations as compared with those without such changes. Leukemias with DNMT3A mutations constituted a group of poor prognosis with elderly disease onset and of promonocytic as well as monocytic predominance among AML-M5 individuals. Screening other leukemia subtypes showed Arg882 alterations in 13.6% of acute myelomonocytic leukemia (AML-M4) cases. Our work suggests a contribution of aberrant DNA methyltransferase activity to the pathogenesis of acute monocytic leukemia and provides a useful new biomarker for relevant cases.
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PMID:Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. 2144 72

This study was purposed to investigate the mutational status of DNA methyltransferase (DNMT3a) gene and the clinical features of AML patients with DNMT3a mutations. Using PCR combined with directly sequencing, the somatic mutations of DNMT3a involving residue of amino acid 882 were detected in 77 AML patients. Furthermore, the clinical features of these patients were also studied. The results showed that the DNMT3a mutation were detected in 7 out of 59 patients with de novo AML (11.9%), which included 4 patients with DNMT3a R882C, 2 patients with DNMT3a R882H and 1 patient with DNMT3a Y874C. Morphology examination indicated that 2 patients were M(2), 1 patient was M(4) and 4 patients were M(5). Cytogenetic analysis revealed that karyotype in 5 out of 7 patients with DNMT3a mutation were normal. In total of 27 patients with normal karyotype 5 patients (22.7%) were found harboring DNMT3a mutation, while no DNMT3a mutation was found in 21 patients with abnormal karyotype. The mutation rate in patients with positive CEBPA was obviously higher than that in patients with negative CEBPA (p = 0.002). Immunophenotype analysis showed that 4 patients (4/7, 57.1%) with DNMT3a mutation expressed lymphoid antigens including CD4 or/and CD7. There were no statistical significance in age, gender, blast cells of bone marrow, white blood cell and platelet counts, hemoglobin level, ratio of CR, mutations of FLT3-ITD, NPM1 and c-kit between patients with DNMT3a mutation and patients with wild DNMT3a (p > 0.05). It is concluded that the DNMT3a mutations are more prevalent in AML patients with normal karyotype accompanying with positive NPM1 and/or CEBPA mutation, the role of DNMT3a mutation in AML prognosis needs to be further studied.
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PMID:[Analysis of DNMT3a gene mutations in acute myelogenous leukemia]. 2151 76

Mutations in DNMT3A encoding DNA methyltransferase 3A were recently described in patients with acute myeloid leukemia. To assess their prognostic significance, we determined the mutational status of DNMT3A exon 23 in 288 patients with AML excluding acute promyelocytic leukemia, aged from 18 to 65 years and treated in Toulouse University Hospital. A mutation was detected in 39 patients (13.5%). All DNMT3A exon 23+ patients had intermediate-risk cytogenetics. Mutations significantly correlated with a higher WBC count (p less than 0.001), NPM1 and FLT3-ITD mutations (p=0.027). DNMT3A mutations were conserved through xenotransplantation in immunodeficient mice. No difference in outcome between DNMT3A exon 23+ and DNMT3A exon 23- patients was found even if the results were stratified by NPM1 or FLT3-ITD status. However, DNMT3A exon 23+ patients had better median DFS (not reached vs 11.6 months, p=0.009) and OS (not reached vs 14.3 months, p=0.005) as compared to DNMT3A exon 23- patients when treated with idarubicin, whereas patients treated with daunorubicin had similar outcome regardless the DNMT3A status. This study shows that DNMT3A mutations have no impact on outcome but could be a predictive factor for response to idarubicin and thus, could have a direct influence in the way AML patients should be managed.
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PMID:Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin? A single center experience. 2208 65

Human acute myeloid leukemia is characterized by a block in maturation caused by genetic and epigenetic alterations. We studied the effects of low concentrations of the DNA methyltransferase (DNMT) inhibitors 5-azacitidine and decitabine on apoptosis and on chromatin remodeling in an AML1/ETO inducible model of human AML. While both DNMT inhibitors induced apoptosis, only azacitidine did so via caspase activation, possibly through its exclusive non-DNA depending effects. We evaluated histone marks for permissive chromatin, H3K4me3, and acetylated histone H4, and for non-permissive chromatin, H3K9me2, and H3K27me3, at the promoter of the IL3 gene, which is under the direct control of AML1/ETO and is critical for myeloid maturation. We observed that low concentrations of DNMT inhibitors induced a loss of H3K27me3 and gain of acetylated histone H4 at the IL3 promoter exclusively in AML1/ETO-positive cells, which was associated with transcriptional reactivation of the IL3 gene.
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PMID:Redistribution of H3K27me3 and acetylated histone H4 upon exposure to azacitidine and decitabine results in de-repression of the AML1/ETO target gene IL3. 2430 Apr 56


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