The role of epigenetics in the regulation of apoptosis in myelodysplastic syndromes and acute myeloid leukemia

Karlic, Heidrun; Herrmann, Harald; Varga, Franz; Thaler, Roman; Reitermaier, René; Spitzer, Silvia; Ghanim, Viviane; Blatt, Katharina; Sperr, Wolfgang R.; Valent, Peter; Pfeilstöcker, Michael

doi:10.1016/j.critrevonc.2013.10.003

Cited by 21 publications

(18 citation statements)

References 140 publications

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“…Downregulation of DNMT1 coinciding with reduced global DNA methylation has been associated with “healthy aging”, and has been implicated to play a role in the development of early MDS (Karlic et al, 2014 ). In contrast, an upregulation of DNMT1 seems to be a transition step to more advanced MDS and AML (Langer et al, 2005 ).…”

Section: Targeting Components Of Epigenetic Transcriptional Regulatiomentioning

confidence: 99%

Digging deep into “dirty” drugs – modulation of the methylation machinery

Pleyer

Greil

2015

Drug Metabolism Reviews

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DNA methylation and histone modification are epigenetic mechanisms that result in altered gene expression and cellular phenotype. The exact role of methylation in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remains unclear. However, aberrations (e.g. loss-/gain-of-function or up-/down-regulation) in components of epigenetic transcriptional regulation in general, and of the methylation machinery in particular, have been implicated in the pathogenesis of these diseases. In addition, many of these components have been identified as therapeutic targets for patients with MDS/AML, and are also being assessed as potential biomarkers of response or resistance to hypomethylating agents (HMAs). The HMAs 5-azacitidine (AZA) and 2′-deoxy-5-azacitidine (decitabine, DAC) inhibit DNA methylation and have shown significant clinical benefits in patients with myeloid malignancies. Despite being viewed as mechanistically similar drugs, AZA and DAC have differing mechanisms of action. DAC is incorporated 100% into DNA, whereas AZA is incorporated into RNA (80–90%) as well as DNA (10–20%). As such, both drugs inhibit DNA methyltransferases (DNMTs; dependently or independently of DNA replication) resulting in the re-expression of tumor-suppressor genes; however, AZA also has an impact on mRNA and protein metabolism via its inhibition of ribonucleotide reductase, resulting in apoptosis. Herein, we first give an overview of transcriptional regulation, including DNA methylation, post-translational histone-tail modifications, the role of micro-RNA and long-range epigenetic gene silencing. We place special emphasis on epigenetic transcriptional regulation and discuss the implication of various components in the pathogenesis of MDS/AML, their potential as therapeutic targets, and their therapeutic modulation by HMAs and other substances (if known). The main focus of this review is laid on dissecting the rapidly evolving knowledge of AZA and DAC with a special focus on their differing mechanisms of action, and the effect of HMAs on transcriptional regulation.

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Section: Targeting Components Of Epigenetic Transcriptional Regulatiomentioning

confidence: 99%

Digging deep into “dirty” drugs – modulation of the methylation machinery

Pleyer

Greil

2015

Drug Metabolism Reviews

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“…The most plausible explanation is that reduced PLCG1 expression in MDS without del(20q) is because of epigenetic dysregulation of the PLCG1 gene. Recent advances in understanding the molecular genetics of MDS revealed the importance of epigenetic dysregulation of genes involved in cell growth, death, and differentiation . The clinical efficacy of hypomethylating agents also suggests that epigenetic dysregulation is important in the molecular pathogenesis of MDS.…”

Section: Discussionmentioning

confidence: 99%

Reduced PLCG1 expression is associated with inferior survival for myelodysplastic syndromes

et al. 2019

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The PLCG1 gene, which encodes the phospholipase C γ1 isoform, is located within the commonly deleted region of the long arm of chromosome 20 (del(20q)) observed in myelodysplastic syndromes (MDS). Phospholipase C is involved in diverse physiological and pathological cellular processes through inositide signaling. We hypothesized that reduced PLCG1 expression because of haploinsufficiency by del(20q) plays a role in the molecular pathogenesis of MDS. Therefore, we analyzed PLCG1 expression in bone marrow mononuclear cells at diagnosis in 116 MDS patients with or without del(20q) by quantitative RT‐PCR to evaluate its clinical significance. The expression level of PLCG1 was significantly lower not only in MDS patients with del(20q) but also in those without del(20q) compared to that of the controls, which suggests that reduced PLCG1 expression is a common molecular event in MDS. Patients in the lowest quartile (Q4) group for PLCG1 expression had lower overall survival (OS) compared to that of other patients (Q1‐Q3) (log‐rank test, P = .0004) with estimated median OS times of 22 in the Q4 group and 106 months in the Q1‐3 group. Univariate and multivariate analysis indicated reduced PLCG1 expression (Q4) was associated with lower OS (hazard ratio 2.58, 95% CI 1.35‐4.84, P = .0049), which suggests that reduced PLCG1 expression is an independent prognostic factor for OS. In addition, patients were well‐stratified for OS by combining PLCG1 expression level (Q4 vs Q1‐3) and bone marrow blast percentage (5% or more vs less than 5%). Thus, the level of PLCG1 expression at time of diagnosis is a prognostic biomarker for MDS.

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“…BCL2L10 is a predictive factor which can predict whether or not a patient will become resistant to AZA (25), so we considered the increased apoptosis of SKM-1 cells was related to BCL-2 downregulation. p16 gene is methylated upon MDS or AML (26). Its high expression in low-risk MDS patients may be associated with ineffective hematopoiesis that results from p16-mediated cell senescence, while its low expressions in high-risk MDS patients may be related with MDS malignant progression (27).…”

Section: Discussionmentioning

confidence: 99%

Silencing HO-1 sensitizes SKM-1 cells to apoptosis induced by low concentration 5-azacytidine through enhancing p16 demethylation

Wang

et al. 2015

International Journal of Oncology

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Heme oxygenase-1 was reported previously as a resistance target on acute myelocytic leukemia (AML). We found that HO-1 was resistant to 5-azacytidine (AZA) treatment of myelodysplastic syndrome (MDS), and explored further the relative mechanisms. Patient bone marrow mononuclear cells (n=48) diagnosed as different levels of MDS were collected. Cell growth was evaluated by MTT assay; cell cycle and apoptosis were detected by flow cytometry; mRNA expression was assessed by real-time PCR, protein expression was analyzed through western blotting. Methylation was assessed by MSP. The survival time, and weight of mice were recorded. HO-1 overexpression was observed in SKM-1 cells after AZA treatment comparing to other cell lines. The HO-1 expression in MDS patients with high-risk was higher than in low-risk patients. After HO-1 was silenced by lentivirus-mediated siRNA, the proliferation of SKM-1 cells was effectively inhibited by low concentration AZA, and the cell cycle was arrested in the G0/G1 phase. Upregulation of p16 and changing of p16-relative cell cycle protein was observed after silencing HO-1 in AZA treated SKM-1 cells. In addition, DNMT1 was downregulated following the decrease of HO-1 expression. In vivo, silencing HO-1 inhibited SKM-1 cell growth induced by AZA in a NOD/SCID mouse model. Silencing HO-1 sensitized SKM-1 cells toward AZA, which may be attributed to the influence of HO-1 on AZA-induced p16 demethylation. HO-1 may be one of the targets that enhance the therapeutic effects of AZA on MDS malignant transformation inspiring new treatment methods for high-risk and very high-risk MDS patients in clinical practice.

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The role of epigenetics in the regulation of apoptosis in myelodysplastic syndromes and acute myeloid leukemia

Cited by 21 publications

References 140 publications

Digging deep into “dirty” drugs – modulation of the methylation machinery

Digging deep into “dirty” drugs – modulation of the methylation machinery

Reduced PLCG1 expression is associated with inferior survival for myelodysplastic syndromes

Silencing HO-1 sensitizes SKM-1 cells to apoptosis induced by low concentration 5-azacytidine through enhancing p16 demethylation

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