Table of Contents
Two general mechanisms have been identified that are involved in the silencing of cancer related genes. Genetic alterations, including mutations and deletions, have been known to be involved in tumor suppression for many years. More recently, DNA methylation has been identified as an additional mechanism to silence genes. Aberrant DNA methylation is an early event in tumorigenesis and a major contributor in the development of solid tumors as well as leukemias. As an epigenetic alteration, DNA methylation does not change the sequence of a gene and thus offers the exciting possibility for therapeutic removal of the methylation group by demethylating drugs.
We are investigating aberrant DNA methylation events in human malignancies with a focus on acute myeloid leukemia, chronic lymphocytic leukemia, lung cancer and head and neck cancer.
Recent findings include the identification of non-random and tumor-type specific methylation changes in human malignancies, the identification of novel cancer related genes preferentially silenced in these malignancies by epigenetic mechanisms and the development of strategies for the identification of epigenetic markers for diagnosis and those with prognostic value.
Furthermore, we have demonstrated that mouse models for human cancer recapitulate epigenetic alteration and thus provide novel tools to investigate mechanisms leading to altered gene regulation through epigenetic changes and thus provide excellent tools to study the early events in tumorigenesis.
With these approaches it should be possible to understand regulation of normal DNA methylation events and to apply this knowledge to better understand the deregulations seen in human cancer.
Major research directions
- Genome–wide scans for DNA methylation in human and mouse malignancies using state-of-the-art profiling protocols e.g. next generation sequencing or methylation arrays
- Cancer gene identification and functional characterization
- Identification of epigenetic biomarkers for diagnosis and prediction
- Mechanisms of epigenetic gene silencing
- Utilize mouse models to study epigenetic mechanisms leading to tumorigenesis
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2. Yu L, Liu C, Vandeusen J, Becknell B, Dai Z, Wu Y, Raval A, Liu T, Ding W, Mao C, Liu S, Smith LT, Lee S, Rassenti L, Marcucci G, Byrd J, Caligiuri MA and Plass C. Global assessment of promoter methylation in a murine model of cancer identifies ID4 as a putative novel tumor suppressor gene in human leukemia. Nature Genetics, 37:265-274, 2005. Abstract
3. Tada Y, Brena RM, Hackanson B, Morrison C, Otterson GA, Plass C. Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein α activity in lung cancer. J Natl Cancer Inst, 98:396-406, 2006. Abstract
4. Raval A, Tanner S, Byrd J, Angerman E, Perko J, Chen S-S, Grever M, Lucas D, Matkovic J, Lin T, Kipps T, Murry F, Weisenburger D, Sanger W, Lynch J, Watson P, Jansen M, Yoshinaga Y, Rosenquist R, de Jong P, Coggill P, Beck S, Lynch H, de la Chapelle A, Plass C. Down-regulation of death associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129:879-890, 2007. Abstract
5. Opavsky R, Wang SH, Trikha P, Raval A, Huang Y, Wu YZ, Rodriguez B, Keller B, Liyanarachchi S, Wei G, Davuluri RV, Weinstein M, Felsher D, Ostrowski M, Leone G, Plass C. CpG island methylation in a mouse model of lymphoma is driven by the genetic configuration of tumor cells. PLoS Genetics 3:1757-1769, 2007. Abstract
6. Brena, R.M., Morrison, C., Liyanarachchi, S., Jarjoura, D., Davuluri, R.V., Otterson, G.A., Reisman, D., Glaros, S., Rush, L.J. and Plass C.: Aberrant DNA Methylation of OLIG1, a Novel Prognostic Factor in Non-Small Cell Lung Cancer. PLoS Med., 4, e108, 2007. Abstract
7. Hackanson B, Bennett KL, Brena RM, Jiang J, Claus R, Chen SS, Blagitko-Dorfs N, Maharry K, Whitman SP, Schmittgen TD, Lübbert M, Marcucci G, Bloomfield CD, Plass C. Epigenetic modification of CCAAT/enhancer binding protein alpha expression in acute myeloid leukemia. Cancer Res. 68: 3142-51, 2008. Abstract
8. Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, Plinkert P, Herpel E, Smiraglia D, Plass C. Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res. 68: 4494-9, 2008. Abstract
9. Flotho C, Claus R, Batz C, Schneider M, Sandrock I, Ihde S, Plass C, Niemeyer CM, Lübbert M. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia, 23:1019-28, 2009. Abstract
10. Chen SS, Raval A, Johnson AJ, Hertlein E, Liu TH, Jin VX, Sherman MH, Liu SJ, Dawson DW, Williams KE, Lanasa M, Liyanarachchi S, Lin TS, Marcucci G, Pekarsky Y, Davuluri R, Croce CM, Guttridge DC, Teitell MA, Byrd JC, Plass C. Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia. Proc Natl Acad Sci USA, 106:13433-13438, 2009. Abstract
11. Goeppert B, Schmezer P, Dutruel C, Oakes C, Renner M, Breinig M, Warth A, Vogel MN, Mittelbronn M, Mehrabi A, Gdynia G, Penzel R, Longerich T, Breuhahn K, Popanda O, Plass C, Schirmacher P, Kern MA. Down-regulation of tumor suppressor A kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms. Hepatology, 52:2023-33, 2010. Abstract
12. Chen SS, Claus R, Lucas DM, Yu L, Qian J, Ruppert AS, West DA, Williams KE, Johnson AJ, Sablitzky F, Plass C, Byrd JC. Silencing of the inhibitor of DNA binding protein 4 (ID4) contributes to the pathogenesis of mouse and human CLL. Blood, 117:862-71, 2011. Abstract
13. Olk-Batz C, Poetsch AR, Nöllke P, Claus R, Zucknick M, Sandrock I, Witte T, Strahm B, Hasle H, Zecca M, Stary J, Bergstraesser E, De Moerloose B, Trebo M, van den Heuvel-Eibrink MM, Wojcik D, Locatelli F, Plass C, Niemeyer CM, Flotho C; European Working Group of Myelodysplastic Syndromes in Childhood (EWOG-MDS). Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome. Blood, 117:4871-80, 2011. Abstract
14. Freedman ML, Monteiro AN, Gayther SA, Coetzee GA, Risch A, Plass C, Casey G, De Biasi M, Carlson C, Duggan D, James M, Liu P, Tichelaar JW, Vikis HG, You M, Mills IG. Principles for the post-GWAS functional characterization of cancer risk loci. Nat. Genet., 43(6):513-8, 2011. Abstract