This research project will study the role of epigenetic DNA regulation, and specifically of Cytosine methylation, in normal B-cell development and lymphomagenesis. The long-term objective for the project is to be able to subclassify the heterogeneous group of Diffuse Large B-cell Lymphomas (DLBCL) based on gene methylation signature into clinically relevant groups and to identify patients, which will be responsive to standard therapy and epigenetic therapy including demethylating agents.
The specific aims i nclude: a) identifying the epigenomic signatures in DLBCLs and subsets of normal B cells using DNA methylation and gene expression profiling, using epigenomic signatures to classify DLBCLs into prognostically and biologically relevant groups;b) identifying the molecular mechanism of normal and aberrant B-cell DNA methylation dependent gene silencing by studying the expression and biological functions of DNA methyltransferases and Methyl Binding proteins;identifying epigenomic signatures predictive of biological dependence on these factors and predictive of response to epigenetic therapy drugs, and testing the therapeutic value of targeting DNMTs and MBDs by using shRNA and small molecules in DLBCL cell lines and primary patient samples. The data will lead to predictive models of clinical and biological behavior of DLBCLs based on the integration of gene expression and epigenetic signatures, will identify epigenomic prognostic markers, identify genes and biological pathways which are responsible for neoplastic transformation of normal lymphocytes and will test the suitability of the epigenetic silencing machinery as potential therapeutic targets in DLBCL, which are most common and biologically heterogeneous group of lymphomas.
to Public Health: This research project will study contribution of non-inheritable DNA modifications to the pathobiology of Lymphomas. We will identify prognostic markers in Diffuse Large B-cell Lymphomas, subclassify lymphomas based on epigenetic signatures and test novel therapies.
|Chambwe, Nyasha; Kormaksson, Matthias; Geng, Huimin et al. (2014) Variability in DNA methylation defines novel epigenetic subgroups of DLBCL associated with different clinical outcomes. Blood 123:1699-708|
|Clozel, Thomas; Yang, ShaoNing; Elstrom, Rebecca L et al. (2013) Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov 3:1002-19|
|Jiang, Yanwen; Hatzi, Katerina; Shaknovich, Rita (2013) Mechanisms of epigenetic deregulation in lymphoid neoplasms. Blood 121:4271-9|
|Shaknovich, Rita; Melnick, Ari (2011) Epigenetics and B-cell lymphoma. Curr Opin Hematol 18:293-9|
|Shaknovich, Rita; Cerchietti, Leandro; Tsikitas, Lucas et al. (2011) DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation. Blood 118:3559-69|
|Oricchio, Elisa; Nanjangud, Gouri; Wolfe, Andrew L et al. (2011) The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma. Cell 147:554-64|
|Cerchietti, Leandro C; Hatzi, Katerina; Caldas-Lopes, Eloisi et al. (2010) BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy. J Clin Invest 120:4569-82|
|Peled, Jonathan U; Yu, J Jessica; Venkatesh, Jeganathan et al. (2010) Requirement for cyclin D3 in germinal center formation and function. Cell Res 20:631-46|
|Velichutina, Irina; Shaknovich, Rita; Geng, Huimin et al. (2010) EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 116:5247-55|
|Shaknovich, Rita; Geng, Huimin; Johnson, Nathalie A et al. (2010) DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma. Blood 116:e81-9|