Epigenetic Regulation In Lymphoid Malignancies

Abstract SCI-28 The past decade has seen an explosion in our knowledge about epigenetic regulation of gene expression in both normal and neoplastic cell renewal. We can increasingly view cancer, including lymphatic malignancies, as diseases driven by both genetic and epigenetic abnormalities. Cancer epigenetics began with focus on alterations in DNA methylation leading to our current knowledge that every individual patient9s tumor harbors hundreds of abnormally, transcriptionally silenced, genes which harbor CpG island hypermethylation in their promoters. Now, we understand that what might be termed the “cancer epigenome” is constituted by many other chromatin aberrations and focus now includes alterations in histone acetylation and other histone modifications, polycomb group protein (PcG) transcriptional repression, and interaction of each of these processes with DNA methylation changes. Additionally, we are increasing our understanding of the molecular processes which initiate and maintain epigenetic abnormalities in cancer by realizing their ties, in multiple ways, to links between chromatin regulation in embryonic stem (ES)/progenitor cells and cancer stem like cells (CSC9s). First, the genes affected with abnormal silencing in cancer include those which affect virtually every key cell signaling pathway common to maintenance of stemness and tumorigenesis including control of the cell cycle and of stem/progenitor cell regulation ( p16, p15 ), the Wnt pathway ( APC, SOX17 ), cell adhesion and invasion ( E-cadherin ), and apoptosis ( DAP-kinase ). Second, there is an emerging concept of a molecular progression of gene silencing during tumorigenesis. This begins with a link to a feature of the embryonic epigenome which is normally responsible for maintaining key ES genes in a low, but poised, transcription state. When associated with cancer, this state may contribute to disruption of normal lineage commitment and differentiation and contribute to abnormal cell expansion in early stages of cancer evolution and to the phenotype of CSC9s. The core of this molecular progression involves initial PcG repression of transcription of genes with promoter CpG islands not normally DNA methylated during development. Abnormal DNA methylation is subsequently imposed upon these promoters in cancer deepening their transcriptional repression. All of these tumor changes may be spurred by cancer risk states including ageing and abnormal cell renewal during chronic inflammation. Multiple translational implications have arisen based on our increasing understanding of the cancer epigenome. First, abnormal gene promoter DNA methylation, and other chromatin changes, can be utilized as potentially powerful biomarkers for cancer risk assessment, early cancer diagnosis, molecular staging of tumors, and monitoring of drug sensitivities. Second, there is current excitement about the promise of “epigenetic therapy” centering around “reprogramming” the cancer epigenome as a molecular target strategy. This has potential as frontline cancer therapy and for treatment of advanced disease. Importantly, cancer epigenetic control of CSC9s has been recently linked to maintenance of their drug resistant phenotypes and to the possibility of reversing this resistance by epigenetic therapies. Disclosures: Baylin: Oncomethylome Sciences: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BioNumerick Pharm: Consultancy, Research Funding; Constellation Pharm: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Progen: Consultancy, Membership on an entity9s Board of Directors or advisory committees.