Article

A Genome-wide screen identifies frequently methylated genes in haematological and epithelial cancers

Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B152TT, UK.
Molecular Cancer (Impact Factor: 5.4). 02/2010; 9:44. DOI: 10.1186/1476-4598-9-44
Source: PubMed

ABSTRACT Genetic as well as epigenetic alterations are a hallmark of both epithelial and haematological malignancies. High throughput screens are required to identify epigenetic markers that can be useful for diagnostic and prognostic purposes across malignancies.
Here we report for the first time the use of the MIRA assay (methylated CpG island recovery assay) in combination with genome-wide CpG island arrays to identify epigenetic molecular markers in childhood acute lymphoblastic leukemia (ALL) on a genome-wide scale. We identified 30 genes demonstrating methylation frequencies of > or =25% in childhood ALL, nine genes showed significantly different methylation frequencies in B vs T-ALL. For majority of the genes expression could be restored in methylated leukemia lines after treatment with 5-azaDC. Forty-four percent of the genes represent targets of the polycomb complex. In chronic myeloid leukemia (CML) two of the genes, (TFAP2A and EBF2), demonstrated increased methylation in blast crisis compared to chronic phase (P < 0.05). Furthermore hypermethylation of an autophagy related gene ATG16L2 was associated with poorer prognosis in terms of molecular response to Imatinib treatment. Lastly we demonstrated that ten of these genes were also frequently methylated in common epithelial cancers.
In summary we have identified a large number of genes showing frequent methylation in childhood ALL, methylation status of two of these genes is associated with advanced disease in CML and methylation status of another gene is associated with prognosis. In addition a subset of these genes may act as epigenetic markers across hematological malignancies as well as common epithelial cancers.

Full-text

Available from: Daniel Catchpoole, Apr 26, 2015
1 Follower
 · 
189 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.
    Oncotarget 11/2014; · 6.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Significance: Chronic myeloid leukemia (CML) involves the malignant transformation of hematopoietic stem cells, defined largely by the Philadelphia chromosome and expression of the BCR-ABL oncoprotein. Pharmacological tyrosine kinase inhibitors (TKIs) including imatinib mesylate, have overcome limitations in conventional treatment for the improved clinical management of CML. Recent Studies: Accumulated evidence has led to the identification of a subpopulation of quiescent leukemia progenitor cells with stem-like self renewal properties that may initiate leukemogenesis, are also shown to be present in residual disease due to their insensitivity to tyrosine kinase inhibition. Critical issues: The characterisation of quiescent leukemia progenitor cells as a unique cell population in CML pathogenesis has become critical with the complete elucidation of mechanisms involved in their survival independent of BCR-ABL important in the development of novel anticancer strategies. Understanding of these functional pathways in CML progenitor cells will allow for their selective therapeutic targeting. In addition, disease pathogenesis and drug responsiveness is also thought to be modulated by epigenetic regulatory mechanisms such as DNA methylation, histone acetylation and microRNA expression, with a capacity to control CML-associated gene transcription. Future Directions: A number of compounds in combination with tyrosine kinase inhibitors are under preclinical and clinical investigation to assess their synergistic potential in targeting leukemic progenitor cells and/or the epigenome in CML. Despite the collective promise, further research is required in order to refine understanding, and ultimately advance antileukemic therapeutic strategies.
    Antioxidants and Redox Signaling 11/2014; DOI:10.1089/ars.2014.6096 · 7.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic modifications have been considered as hallmarks of cancer and play an important role in tumor initiation and development. Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, may regulate cell cycle and apoptosis, as well as macroautophagy (hereafter referred to as autophagy). Autophagy, as a crucial cellular homeostatic mechanism, performs a dual role, having pro-survival or pro-death properties. A variety of signaling pathways including epigenetic control have been implicated in the upregulation or downregulation of autophagy. However, the role of epigenetic regulation in autophagy is still less well acknowledged. Recent studies have linked epigenetic control to the autophagic process. Some epigenetic modifiers are also involved in the regulation of autophagy and potentiate the efficacy of traditional therapeutics. Thus, understanding the novel functions of epigenetic control in autophagy may allow us to develop potential therapeutic approaches for cancer treatment. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 02/2015; 360(2). DOI:10.1016/j.canlet.2015.02.009 · 5.02 Impact Factor