Hypermethylation of the p15INK4B gene promoter in B‐chronic lymphocytic leukemia

Papageorgiou, Sotirios; Lambropoulos, S; Pappa, Vassiliki; Economopoulou, Christina; Kontsioti, Frieda; Papageorgiou, Efstathios; Tsirigotis, Panagiotis; Dervenoulas, John; Economopoulos, Theofanis

doi:10.1002/ajh.20914

Cited by 14 publications

(7 citation statements)

References 9 publications

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“…Methylation of the p15 ink4b Promoter Is Dependent on the ZNF217/CoREST Complex The human p15 ink4b promoter contains a CpG island within 1 kb of the TSS, which is highly methylated in many cancer cell lines (Aggerholm et al, 2006;Papageorgiou et al, 2007) and also contains the ZNF217/CoREST binding region ( Figure 1A). To assess whether the ZNF217/CoREST complex influences the DNA methylation of the p15 ink4b gene, we carried out knockdown experiments and assessed the methylation status of the p15 ink4b promoter by sodium bisulphite sequencing and methylation-specific PCR.…”

Section: Molecular Cellmentioning

confidence: 99%

“…Aberrant transcriptional silencing of p15 ink4b involving promoter DNA hypermethylation is frequently associated with hematologic and other cancers (Aggerholm et al, 2006;Papageorgiou et al, 2007;Tsellou et al, 2005). Nevertheless, in many cell types TGF-b as well as other stimuli rapidly induce p15 ink4b expression, suggesting that mechanisms are in place for reversing DNA methylation (Gomis et al, 2006a(Gomis et al, , 2006bWarner et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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TGF-β-Dependent Active Demethylation and Expression of the p15ink4b Tumor Suppressor Are Impaired by the ZNF217/CoREST Complex

et al. 2012

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In this study we examine the mechanisms of dynamic DNA methylation of the p15(ink4b) tumor suppressor gene. Using conventional ChIP and ChiPseq, we identify the p15(ink4b) promoter as a target for the ZNF217 oncogene, the CoREST complex, and DNMT3A. Treatment of cells with TGF-β triggers active demethylation involving loss of ZNF217/CoREST/DNMT3A and the corecruitment of SMAD2/3, CBP, and the DNA glycosylase TDG. Knockdown of TDG, or its functional homolog MBD4, prevents TGF-β-dependent demethylation of p15(ink4b). DNA immunoprecipitation of 5mC and 5hmC indicates that 5mC undergoes conversion to 5hmC prior to activation of p15(ink4b). Remarkably, overexpression of ZNF217 inhibits active demethylation and expression of the p15(ink4b) gene by preventing recruitment of SMAD2/3 and TDG. These findings suggest that active demethylation is essential for regulating a subset of TGF-β-dependent genes. Importantly, disruption of active demethylation by the ZNF217 oncogene may be a paradigm for other oncogenic signals on DNA methylation dynamics.

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Section: Molecular Cellmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TGF-β-Dependent Active Demethylation and Expression of the p15ink4b Tumor Suppressor Are Impaired by the ZNF217/CoREST Complex

et al. 2012

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“…In this respect, epigenetic evolution has been observed in relapsed patients compared to pre-treated patients [76]. However, various tumor suppressor genes have been described as being highly methylated, with a correlation to disease stages and/or prognosis, including the Krüppel-like factor 4 (KLF4) gene [77], p15 [78], and Patched (PTCH) [79]. The tumor suppressor PHLPP1 (phosphatase PH domain leucin-rich repeat protein phosphatase) is an important tumor suppressor that directly regulates the Protein kinase B (PKB), also known as Akt kinase [80].…”

Section: Promoters' Hypermethylationmentioning

confidence: 99%

Tumor Suppressors in Chronic Lymphocytic Leukemia: From Lost Partners to Active Targets

Andreani

Carrà

Lingua

et al. 2020

Cancers

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Tumor suppressors play an important role in cancer pathogenesis and in the modulation of resistance to treatments. Loss of function of the proteins encoded by tumor suppressors, through genomic inactivation of the gene, disable all the controls that balance growth, survival, and apoptosis, promoting cancer transformation. Parallel to genetic impairments, tumor suppressor products may also be functionally inactivated in the absence of mutations/deletions upon post-transcriptional and post-translational modifications. Because restoring tumor suppressor functions remains the most effective and selective approach to induce apoptosis in cancer, the dissection of mechanisms of tumor suppressor inactivation is advisable in order to further augment targeted strategies. This review will summarize the role of tumor suppressors in chronic lymphocytic leukemia and attempt to describe how tumor suppressors can represent new hopes in our arsenal against chronic lymphocytic leukemia (CLL).

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“…INK4A [96] and p15 INK4B [97] genes have also been described in small proportion of CLL patients, however the clinical significance from these small studies are yet undefined.…”

Section: Methylation Of P16mentioning

confidence: 99%

Aberrant Methylation in Hematological Malignancies

Thirukonda¹,

Raghupathy²,

Parekh³

2012

Translational

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Epigenetics encompasses heritable changes in gene expression without alterations in genetic sequence. Among the multiple epigenetic regulators of gene expression, methylation of cytosine in genomic DNA is amongst the most stable and best studied. Expanding knowledge of aberrant methylation in hematological malignancies has increased its applicability in diagnosis, classification, prognostication and prediction of treatment response. Genome-wide methylation profiling can differentiate between clinically relevant subtypes of non-hodgkin's lymphoma (NHL) as well as distinguish monoclonal gammopathy of unknown significance (MGUS) from multiple myeloma (MM). New subcategories of normal karyotype acute myeloid leukemia (AML) with distinct canonical pathways and different disease behavior have also been identified by methylation studies. Methylation scores can predict outcomes in chronic lymphocytic leukemia (CLL). Genes with tumor suppressor function are frequently silenced by methylation and may be amenable to therapeutic intervention. DNA hypomethylating agents azacitidine and decitabine have been approved by the FDA for treatment of myelodysplastic syndrome (MDS). Clinical trials of newer agents including histone deacetylase inhibitors (HDAC-i) are showing great promise in different hematological malignancies. High-resolution methylation analysis using massively parallel sequencing (MPS) is likely to further improve our understanding of disease pathogenesis and identify novel therapeutic approaches in hematological malignancies. In this review article we will describe recent advances in methylation studies and the current and potential future impact of this knowledge on management of hematological malignancies.

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Hypermethylation of the p15^INK4B gene promoter in B‐chronic lymphocytic leukemia

Cited by 14 publications

References 9 publications

TGF-β-Dependent Active Demethylation and Expression of the p15ink4b Tumor Suppressor Are Impaired by the ZNF217/CoREST Complex

TGF-β-Dependent Active Demethylation and Expression of the p15ink4b Tumor Suppressor Are Impaired by the ZNF217/CoREST Complex

Tumor Suppressors in Chronic Lymphocytic Leukemia: From Lost Partners to Active Targets

Aberrant Methylation in Hematological Malignancies

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