Epigenetic Modifications in Acute Myeloid Leukemia: Prognosis, Treatment, and Heterogeneity

Goldman, Samantha L.; Hassan, Ciaran; Khunte, Mihir; Soldatenko, Arielle; Jong, Yunji; Afshinnekoo, Ebrahim; Mason, Christopher E.

doi:10.3389/fgene.2019.00133

Cited by 70 publications

(58 citation statements)

References 182 publications

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“…AML is complex disease with a diverse genetic landscape. Recent studies have revealed that epigenetic dysregulation plays an important role in leukaemia pathogenesis [6,11]. Further histone-modifying enzymes reportedly contribute to leukaemia pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Luks-pv Induces Apoptosis Through Methyltransferase Set8 in Human Acute Myeloid Leukaemia Cells

Shi

Ding

et al. 2020

Preprint

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Background We previously reported that LukS-PV induces apoptosis in human acute myeloid leukaemia (AML) cells. Furthermore, SET8 is a member of the SET domain-containing methyltransferase family and overexpressed in numerous tumours, including AML and indicated a poor prognosis. However, it is unclear whether LukS-PV induce apoptosis via SET8. In current study, we aimed to investigate the regulatory mechanisms of SET8 and effects on AML cells under the LukS-PV.Methods Flow cytometry was performed to detect apoptosis in AML primary blasts/cell lines treated with LukS-PV and invasion of AML cells in vivo. The expression of SET8 was quantified through reverse-transcription PCR and western blotting. Chromatin-immunoprecipitation (ChIP) sequencing and bioinformatic methods was performed to explore transcriptional target genes which regulated by SET8-H4K20me1 axis. All experiments were performed in triplicate, and all statistical analyses were conducted using SPSS 16.0.Results In this research, we found that LukS-PV induce cell apoptosis in vitro and inhibit cell invasion in vivo. Our results further confirmed SET8 and H4K20me1 were downregulated in LukS-PV-treated AML cells. Furthermore, we confirmed that LukS-PV induced apoptosis via downregulating SET8/H4K20me1. Finally, Genome-wide analysis identified PIK3CB is the target gene for cell apoptosis mediated by SET8/H4K20me1. In a nutshell, LukS-PV induces apoptosis via the PIK3CB/PI3K/AKT/FOXO1 signal pathway by targeting SET8.Conclusions The present results indicate that LukS-PV induces apoptosis in AML cells by downregulating SET8 and regulating downstream molecular targets, suggesting that SET8 is a potential target for AML therapy using LukS-PV for anti-leukaemia treatment.

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Section: Discussionmentioning

confidence: 99%

Luks-pv Induces Apoptosis Through Methyltransferase Set8 in Human Acute Myeloid Leukaemia Cells

Shi

Ding

et al. 2020

Preprint

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“…According to data from The Cancer Genome Atlas Network (2013), the count of genomic mutations tends to be less in AML than in other cancers (33). Moreover, a similar distribution of mutations was observed before and after progression, but methylation pro le shifts and have a functional impact on gene regulation(34), suggesting the increasing signi cance of understanding epigenetic changes in AML.…”

Section: Discussionmentioning

confidence: 99%

Identification of Aberrantly Methylated and Silenced Genes in Acute Myeloid Leukemia by Combined Methylation/expression Analysis

Guo

Zhang

et al. 2020

Preprint

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Background Aberrant genomic methylation plays an important role in pathogenic process of acute myeloid leukemia (AML) by silencing tumor suppressor genes (TSG). While the key aberrantly methylated genes and related pathways have not been well understood yet, which we aimed to reveal by combined analysis of methylation and expression datasets. The prognostic significance was validated by survival analysis derived from TCGA database. Methods Micro-array data of GSE 15061 and GSE58477 were downloaded from Gene Expression Omnibus (GEO) database. The differentially methylated regions (DMR) and differentially expressed genes (DEG) were identified using R program (R 3.6.1). Over-representation analysis was performed to obtain the enriched biological processes and pathways. Cox hazards analysis was employed to select the genes significantly associated with AML survival, using the data derived from the Cancer Genome Atlas (TCGA) database. Subgroup analysis, regarding induction type, was conducted to identify biomarkers for HMA treatment. Furthermore, SYNJ2 associated genome-wide gene/miRNA expression and methylation profile were explored. Results A total of 198 aberrant methylation related underexpressed genes were identified. Univariable analysis revealed methylation level of 6 out of 198 genes (CORO1A/MPO/SYNJ2/EHD1/GAS2L1/SLC11A1) were significantly associated with AML survival. SYNJ2 methylation was an independent predictor for OS. Notably, subgroup analysis revealed hypermethylation of CORO1A predicted better OS in HMA group. Further gene set enrichment analysis indicated SYNJ2-associated activation of PI3K-Akt/NF-kappaB/JAK-STAT signaling and checkpoint pathway. The microRNAs, such as miR217/miR485-3p/miR-889-3p, were downregulated in SYNJ2-hypermethylated group, leading to potential HOXA13 upregulation. Conclusion The prognostic methylation signature was revealed in our studies, and SYNJ2 was proved as an independent prognostic factor. Methylation of CORO1A may serve as biomarker for HMA treatment in AML.

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“…AML is a very heterogeneous disease and this heterogeneity has been demonstrated both by cytogenetic and molecular genetic analyses as well as gene expression, epigenetic, and possibly also proteomic and metabolic profiling [ 12 , 43 , 44 , 45 , 46 , 47 , 48 ]. The most important factors for evaluation of AML relapse risk in routine clinical practice are the cytogenetic and the molecular genetic abnormalities (these and other prognostic factors are gathered in Table 1 ).…”

Section: Aml Heterogeneity and Prognostic Evaluationmentioning

confidence: 99%

The Implementation of Mass Spectrometry-Based Proteomics Workflows in Clinical Routines of Acute Myeloid Leukemia: Applicability and Perspectives

Hernandez-Valladares

Bruserud

Selheim

2020

IJMS

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With the current reproducibility of proteome preparation workflows along with the speed and sensitivity of the mass spectrometers, the transition of the mass spectrometry (MS)-based proteomics technology from biomarker discovery to clinical implementation is under appraisal in the biomedicine community. Therefore, this technology might be implemented soon to detect well-known biomarkers in cancers and other diseases. Acute myeloid leukemia (AML) is an aggressive heterogeneous malignancy that requires intensive treatment to cure the patient. Leukemia relapse is still a major challenge even for patients who have favorable genetic abnormalities. MS-based proteomics could be of great help to both describe the proteome changes of individual patients and identify biomarkers that might encourage specific treatments or clinical strategies. Herein, we will review the advances and availability of the MS-based proteomics strategies that could already be used in clinical proteomics. However, the heterogeneity of complex diseases as AML requires consensus to recognize AML biomarkers and to establish MS-based workflows that allow their unbiased identification and quantification. Although our literature review appears promising towards the utilization of MS-based proteomics in clinical AML in a near future, major efforts are required to validate AML biomarkers and agree on clinically approved workflows.

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Epigenetic Modifications in Acute Myeloid Leukemia: Prognosis, Treatment, and Heterogeneity

Cited by 70 publications

References 182 publications

Luks-pv Induces Apoptosis Through Methyltransferase Set8 in Human Acute Myeloid Leukaemia Cells

Luks-pv Induces Apoptosis Through Methyltransferase Set8 in Human Acute Myeloid Leukaemia Cells

Identification of Aberrantly Methylated and Silenced Genes in Acute Myeloid Leukemia by Combined Methylation/expression Analysis

The Implementation of Mass Spectrometry-Based Proteomics Workflows in Clinical Routines of Acute Myeloid Leukemia: Applicability and Perspectives

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