Possible role of intragenic DNA hypermethylation in gene silencing of the tumor suppressor gene NR4A3 in acute myeloid leukemia

Idiopathic Parkinson's disease and manganese-induced atypical parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the Parkinson's disease toxin 1-methyl-4-phenylpyridinium ion (MPP ) and manganese (Mn), followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~ 93%) with slow discharge rates (0-5 Hz). While MPP exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High-throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-signal transducer and activator of transcription pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the Janus kinase-signal transducer and activator of transcription pathway. We conclude that idiopathic Parkinson's disease and atypical parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. Cover Image for this issue: doi. 10.1111/jnc.13821.

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“…; Shimizu et al . ). The amplified region included 16 CpG sites of which nine were studied by two independent pyrosequencing runs.…”

Section: Resultsmentioning

confidence: 97%

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

Mythri

Raghunath

Narwade

et al. 2017

Journal of Neurochemistry

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“…DNA methyltransferases (DNMT) are the enzymes which are known to cause aberrant DNA methylation leading to epigenetic silencing of normal genes which may contribute to the pathogenesis of cancer including leukemia by altering differentiation, proliferation, and apoptosis [10][11][12]. DNA hypermethylation suppresses the expression of several tumor suppressor genes by affecting their promoter region [13,14]. Two azanucleoside DNMT inhibitors, azacytidine (5azacytidine) and decitabine (5-aza-2'-deoxycytidine) have shown significant efficacy in patients with MDS [15,16].…”

Section: Introductionmentioning

confidence: 99%

Use of decitabine for patients with refractory or relapsed acute myeloid leukemia: a systematic review and meta-analysis

Zhao

Liu

et al. 2019

Hematology

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Background: Approximately, one-third of adult patients with acute myeloid leukemia (AML) are refractory to initial induction chemotherapy and relapse occurs in most patients who achieve remission. This study evaluates the efficacy of decitabine in the management of refractory or relapsed AML. Methods: After literature search in electronic databases (Google Scholar, Embase, Ovid, and PubMed) studies were selected by following predetermined eligibility criteria. Randomeffects meta-analyses were performed to achieve effect sizes of complete remission (CR) rate, response rate (RR), and median survival after therapy. Subgroup analyses were performed with regards to use of decitabine with either epigenetics-based therapy, molecular therapy or chemotherapy. Results: Twenty studies were included (310 patients; age 55.1 years [95% confidence interval (CI): 43.8, 66.4]; 57% [52%, 63%] males). Overall RR was 46.1% [95% CI: 36.1%, 56.1%]. Overall CR rate was 23.5% [95% CI: 22.1%, 24.9%] but was 14.85% [95% CI: 3.8%, 25.9%] for decitabine with epigenetics-based therapies, 15.4% [95% CI: 6.7%, 24.0%] for decitabine with immunotherapy or molecular therapy, 34.8% [95% CI: 18.7%, 50.9%] for decitabine with chemotherapy, and 37.5% [36.4%, 38.7%] for decitabine with chemotherapy and molecular therapy. Median survival was 7.2 months [95% CI: 5.17, 9.3]. Major adverse events were neutropenia, nausea/vomiting, infections, fatigue, febrile neutropenia, diarrhea, thrombocytopenia, anemia, anorexia, leukopenia, hemorrhage, and hyperglycemia. Conclusion: Decitabine in combination with chemotherapy or molecular therapy has shown efficacious properties in refractory or relapsed AML patients.

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“…From our study, although some of these genes methylation (such as S0 × 17 and RAP1GAP) was previously reported in MDS [31,32], the majority of them were unknown so far. Interestingly, some of them were reported to be methylated in other blood cancers or solid tumors, such as HOXD11, GBX2, CRMP1, RBM47, NHLRC1, WNT2, TUSC3, NRG1, TSPYL5, CNTFR, NR4A3, PHOX2A, KCNA5, PTGDR, HS3ST2, CLDN7, CPT1C, and NKX2-4 [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. Based on these ndings, we further selected the unreported hypermethylated genes with potential roles involved in MDS progression for further validation.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Methylation Sequencing Identifies Progression-Related Epigenetic Drivers in Myelodysplastic Syndromes

Zhou

Zhang²,

Xu³

et al. 2020

Preprint

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Background: The mechanism underlying disease progression of myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) remains poorly elucidated. Epigenetic alterations are increasingly implicated in the pathogenesis of cancer progression including MDS. However, little studies explored the whole-genome methylation alterations during MDS progression.Methods: We conducted reduced representation bisulfite sequencing in four paired MDS/secondary AML (MDS/sAML) patients and intended to discover methylation-associated epigenetic drivers in MDS progression.Results: In four paired MDS/sAML patients, cases at sAML stage showed significantly increased methylation level when compared with their matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involved in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were identified involved in MDS progression. Further targeted bisulfite sequencing identified aberrant GFRA1, IRX1, NPY, and ZNF300 methylation was frequent events in additional de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Moreover, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was further confirmed by real-time quantitative methylation-specific PCR. Clinical studies showed that ZNF300 methylation could act as a potential biomarker helpful for the diagnosis and prognosis in MDS and AML patients. In in vitro experiments, overexpression of ZNF300 exhibited anti-proliferative and pro-apoptotic effects in MDS-derived AML cell line SKM-1.Conclusions: Genome-wide DNA hypermethylation was a frequent event during MDS progression. Among these changes, ZNF300 methylation through the regulation of ZNF300 expression acted as an epigenetic driver in MDS progression. These findings give a theoretical basis for investigating and using the efficacy of DNMT inhibitors in MDS patients against disease progression, and provide new insights for targeted therapy in MDS.

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Possible role of intragenic DNA hypermethylation in gene silencing of the tumor suppressor gene NR4A3 in acute myeloid leukemia

Cited by 17 publications

References 41 publications

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

Use of decitabine for patients with refractory or relapsed acute myeloid leukemia: a systematic review and meta-analysis

Genome-Wide Methylation Sequencing Identifies Progression-Related Epigenetic Drivers in Myelodysplastic Syndromes

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