CpG island methylator phenotype of myelodysplastic syndrome identified through genome‐wide profiling of <scp>DNA</scp> methylation and gene expression

Zhao, Xiaoli; Yang, Feng Chun; Li, Shuang; Liu, Meixia; Shi, Ying; Jia, Xiaodong; Wang, Xiaoqin

doi:10.1111/bjh.12811

Cited by 25 publications

(32 citation statements)

References 48 publications

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“…Nonetheless, the differentially methylated genes specific in the combination treatment underline the important contribution of demethylation to the synergistic effect. This profile might serve as the basis for the identification of a methylation signature that is predictive of clinical response as shown in myelodysplastic syndrome (49) or to a limited extent suggested recently in CTCL (50).…”

Section: Discussionmentioning

confidence: 94%

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Rozati

Cheng

Widmer

et al. 2016

Clinical Cancer Research

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Purpose: Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies that despite available therapies commonly relapse. The emergence of combination epigenetic therapies in other hematologic malignancies have made investigation of such combinations in CTCL a priority. Here, we explore the synergistic antiproliferative effects of romidepsin, an HDAC inhibitor, and azacitidine, a demethylating agent, combination in CTCL.Experimental Design: The growth inhibition under combination treatment and single agent was explored by the MTT cell viability assay and the Annexin V/propidium iodide (PI) apoptosis assay in different CTCL cell lines and tumor cells derived from S ezary syndrome patients. Quantitative analysis of a dose-effect relationship of romidepsin and azacitidine was done by the CompuSyn software. Investigation of mechanism of action was performed by flow cytometry, immunoblotting, qRT-PCR arrays, and chromatin immunoprecipitation. Global CpG methylation sequencing was utilized to study genome methylation alteration under the treatment modalities.Results: The combination of romidepsin and azacitidine exerts synergistic antiproliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL cell lines and tumor cells derived from S ezary syndrome patients. We identified genes that were selectively induced by the combination treatment, such as the tumor suppressor gene RhoB that is linked to enhanced histone acetylation at its promoter region in parallel with pronounced expression of p21. Global CpG methylation sequencing in a CTCL cell line and tumor cells demonstrated a subset of genes with a unique change in methylation profile in the combination treatment.Conclusions: The synergistic antiproliferative effects of romidepsin and azacitidine combination treatment justify further exploration in clinical trials for advanced CTCL.

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Section: Discussionmentioning

confidence: 94%

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Rozati

Cheng

Widmer

et al. 2016

Clinical Cancer Research

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“…Both of these findings suggest a link between iron and leukemogenesis. Concerning the mechanism, DNA methylation is considered to be associated with the pathogenesis and exacerbation of MDS [23][24][25][26][27]. In this study, we first demonstrated that iron overload activated the ACO1-IDH pathway in the TCA cycle and led to increased 2-HG activity, which induced DNA methylation, a critical epigenetic aberration process.…”

Section: Discussionmentioning

confidence: 68%

“…α-KG acts as a substrate of the TCA cycle, whereas it is utilized in many other reactions including DNA demethylation [20,21]. Recently, IDH mutation and the up-regulation of DNA methylation were also predicted to be independent prognosis factors in patients with MDS [22][23][24][25][26][27]. Therefore, the mechanism of aberrant DNA methylation in patients with MDS is to be elucidated further.…”

Section: Introductionmentioning

confidence: 99%

Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

et al. 2016

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Iron overload remains a concern in myelodysplastic syndrome (MDS) patients. Iron chelation therapy (ICT) thus plays an integral role in the management of these patients. Moreover, ICT has been shown to prolong leukemia-free survival in MDS patients; however, the mechanisms responsible for this effect are unclear. Iron is a key molecule for regulating cytosolic aconitase 1 (ACO1). Additionally, the mutation of isocitrate dehydrogenase (IDH), the enzyme downstream of ACO1 in the TCA cycle, is associated with epigenetic abnormalities secondary to 2-hydroxyglutarate (2-HG) and DNA methylation. However, epigenetic abnormalities observed in many MDS patients occur without IDH mutation. We hypothesized that iron itself activates the ACO1-IDH pathway, which may increase 2-HG and DNA methylation, and eventually contribute to leukemogenesis without IDH mutation. Using whole RNA sequencing of bone marrow cells in iron-overloaded mice, we observed that the enzymes, phosphoglucomutase 1, glycogen debranching enzyme, and isocitrate dehydrogenase 1 (Idh1), which are involved in glycogen and glucose metabolism, were increased. Digital PCR further showed that Idh1 and Aco1, enzymes involved in the TCA cycle, were also elevated. Additionally, enzymatic activities of TCA cycle and methylated DNA were increased. Iron chelation reversed these phenomena. In conclusion, iron activation of glucose metabolism causes an increase of 2-HG and DNA methylation.

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“…The CIMP-high phenotype has been associated with an adverse prognosis in clear cell carcinoma of the kidney (Arai et al 2012), melanoma (Tanemura et al 2009), and myelodysplastic syndrome (Zhao et al 2014). By contrast, a methylation analysis of a large set of breast cancer cohort recently demonstrated a lower risk for metastatic failure in the CIMPpositive group (Fang et al 2011).…”

Section: The Cpg Island Methylator Phenotype In Cancermentioning

confidence: 99%

A decade of DNA methylation profiling in cancer: What have we learned?

Sharma

Kuerbitz

2015

MRAJ

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Abstract-Investigators have studied DNA methylation in tumor cells for nearly 50 years. Differences in gene-specific methylation between cancer cells and their normal counterparts were described more than 30 years ago. From early techniques that measured overall DNA methylation levels to enzyme-associated techniques that interrogated methylation at a single CpG dinucleotide to present day assays that catalogue the methylation of every cytosine in the genome, technical advancement progressively has brought increasing clarity to our understanding of the complex epigenomes of normal and neoplastic cells. Over the past 10 years we have been witness to an explosion of investigation into the epigenetic basis of cancer, and application of the powerful genome-wide DNA methylation profiling techniques to be reviewed have yielded critical insights into the organization of the cancer methylome with its broad regions of hypomethylation and foci of hypermethylation resulting in critical differences in gene expression and chromosomal stability compared to normal cells. These insights, in turn, have prompted novel, testable hypotheses, to be discussed, pertaining to fundamental aspects of cancer biology including the potential stem cell/progenitor cell origins of cancer and the plasticity of gene expression that may underlie tumor heterogeneity and tumor progression. Finally to be discussed is the growing portfolio of epigenetic tools being provided by modern methylome profiling analyses. These biomarker tools are complementing and extending the current genomic tests that are improving cancer diagnosis and that increasingly will facilitate highly individualized cancer treatment in the upcoming decade.

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CpG island methylator phenotype of myelodysplastic syndrome identified through genome‐wide profiling of DNA methylation and gene expression

Cited by 25 publications

References 48 publications

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

A decade of DNA methylation profiling in cancer: What have we learned?

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