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      Downregulation of Death-Associated Protein Kinase 1 ( DAPK1) in Chronic Lymphocytic Leukemia

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          Summary

          The heritability of B cell chronic lymphocytic leukemia (CLL) is relatively high; however, no predisposing mutation has been convincingly identified. We show that loss or reduced expression of death-associated protein kinase 1 ( DAPK1) underlies cases of heritable predisposition to CLL and the majority of sporadic CLL. Epigenetic silencing of DAPK1 by promoter methylation occurs in almost all sporadic CLL cases. Furthermore, we defined a disease haplotype, which segregates with the CLL phenotype in a large family. DAPK1 expression of the CLL allele is downregulated by 75% in germline cells due to increased HOXB7 binding. In the blood cells from affected family members, promoter methylation results in additional loss of DAPK1 expression. Thus, reduced expression of DAPK1 can result from germline predisposition, as well as epigenetic or somatic events causing or contributing to the CLL phenotype.

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          CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future.

          Manel Esteller (2002)
          We have come a long way since the first reports of the existence of aberrant DNA methylation in human cancer. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. CpG island hypermethylation has been described in almost every tumor type. Many cellular pathways are inactivated by this type of epigenetic lesion: DNA repair (hMLH1, MGMT), cell cycle (p16(INK4a), p15(INK4b), p14(ARF)), apoptosis (DAPK), cell adherence (CDH1, CDH13), detoxification (GSTP1), etc em leader However, we still know little of the mechanisms of aberrant methylation and why certain genes are selected over others. Hypermethylation is not an isolated layer of epigenetic control, but is linked to the other pieces of the puzzle such as methyl-binding proteins, DNA methyltransferases and histone deacetylase, but our understanding of the degree of specificity of these epigenetic layers in the silencing of specific tumor suppressor genes remains incomplete. The explosion of user-friendly technologies has given rise to a rapidly increasing list of hypermethylated genes. Careful functional and genetic studies are necessary to determine which hypermethylation events are truly relevant for human tumorigenesis. The development of CpG island hypermethylation profiles for every form of human tumors has yielded valuable pilot clinical data in monitoring and treating cancer patients based in our knowledge of DNA methylation. Basic and translational will both be needed in the near future to fully understand the mechanisms, roles and uses of CpG island hypermethylation in human cancer. The expectations are high.
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            Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry.

            Mathias Ehrich, Matthew R. Nelson, Patrick Stanssens … (2005)
            Methylation is one of the major epigenetic processes pivotal to our understanding of carcinogenesis. It is now widely accepted that there is a relationship between DNA methylation, chromatin structure, and human malignancies. DNA methylation is potentially an important clinical marker in cancer molecular diagnostics. Understanding epigenetic modifications in their biological context involves several aspects of DNA methylation analysis. These aspects include the de novo discovery of differentially methylated genes, the analysis of methylation patterns, and the determination of differences in the degree of methylation. Here we present a previously uncharacterized method for high-throughput DNA methylation analysis that utilizes MALDI-TOF mass spectrometry (MS) analysis of base-specifically cleaved amplification products. We use the IGF2/H19 region to show that a single base-specific cleavage reaction is sufficient to discover methylation sites and to determine methylation ratios within a selected target region. A combination of cleavage reactions enables the complete evaluation of all relevant aspects of DNA methylation, with most CpGs represented in multiple reactions. We successfully applied this technology under high-throughput conditions to quantitatively assess methylation differences between normal and neoplastic lung cancer tissue samples from 48 patients in 47 genes and demonstrate that the quantitative methylation results allow accurate classification of samples according to their histopathology.
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              Molecular Diagnosis of Primary Mediastinal B Cell Lymphoma Identifies a Clinically Favorable Subgroup of Diffuse Large B Cell Lymphoma Related to Hodgkin Lymphoma

              Andreas Rosenwald, George Wright, Karen Leroy … (2003)
              Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.
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                Author and article information

                Contributors
                Albert de la Chapelle
                Christoph Plass
                Journal
                Journal ID (nlm-ta): Cell
                Journal ID (iso-abbrev): Cell
                Title: Cell
                Publisher: Cell Press
                ISSN (Print): 0092-8674
                ISSN (Electronic): 1097-4172
                Publication date PMC-release: 01 June 2007
                Publication date (Print): 01 June 2007
                Volume: 129
                Issue: 5
                Pages: 879-890
                Affiliations
                [1 ]Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, The Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43214, USA
                [2 ]Department of Internal Medicine, Division of Hematology and Oncology, The Ohio State University, Columbus, OH 43214, USA
                [3 ]Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
                [4 ]Department of Preventive Medicine and Public Health, Creighton University, Omaha, NB 68178, USA
                [5 ]Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK
                [6 ]Department of Internal Medicine, University of California at San Diego, San Diego, CA, 92093, USA
                [7 ]Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden
                [8 ]Department of Hematology/Oncology, University of Freiburg Medical Center, Freiburg, Germany
                Author notes
                [∗ ]Corresponding author albert.delachapelle@ 123456osumc.edu
                [∗∗ ]Corresponding author christoph.plass@ 123456osumc.edu
                [9]

                Present address: The Ohio State University, Human Cancer Genetics Program, Tzagournis Medical Research Facility 464A, 420 West 12th Avenue, Columbus, OH 43210, USA.

                [10]

                Present address: Department of Oncology, CCSR 2250, Stanford University, Stanford, CA 94305, USA.

                Article
                Publisher ID: S0092-8674(07)00512-0
                DOI: 10.1016/j.cell.2007.03.043
                PMC ID: 4647864
                PubMed ID: 17540169
                SO-VID: a33eda23-44f7-4765-b2aa-ce60645eb27a
                Copyright © © 2007 Elsevier Inc.
                History
                Date received : 20 September 2006
                Date revision received : 15 January 2007
                Date accepted : 12 March 2007
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: humdisease
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: humdisease

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