Abstract Dysregulated epigenome has emerged as the hallmark of cancers. For instance, more than 80% of diffuse large B cell lymphoma (DLBCL) carries the mutation in at least one epigenetic regulator, including TET2. TET proteins (Ten-Eleven Translocation; TET1, TET2, TET3) are dioxygenases that oxidize the methyl group of 5- methylcytosine (5mC) primarily to 5-hydroxymethylcytosine (5hmC), a stable epigenetic mark and an essential intermediate for DNA demethylation. Despite TET mutation strongly associates with cancers, the mechanism by which TET proteins suppress cell transformation is not well understood. Mutation of Tet resulted in dysregulated B cell proliferation. Unexpectedly, TET-mutation in B cells affects T cells in trans and creates a microenvironment permissive to cell transformation. In this K22 proposal, I will extend these studies to investigate the role of TET enzymes in regulating the epigenome of GC B cells and their malignant transformation into DLBCL. Specifically, I will test the hypothesis that TET proteins prevent B lymphomagenesis by cell-intrinsically regulating the epigenome of B cells and extrinsically affecting the bystander T cells. To address this hypothesis, I propose the following Specific Aims. In Aim 1, I will profile the hydroxymethylome and define the TetEs normal and transformed germinal center B cells from mouse and human. In Aim2, I will investigate the functional collaboration between TET and other epigenetic regulators. I will also use a novel proteomics approach to analyze locus-specific proteomics at TetEs. In Aim 3, I will examine unexpected crosstalk between Tet-deficient B cells and T cells. This K22 proposal will allow me to acquire the necessary skills to be an independent investigator. Completion of this proposal will provide significant insight into the molecular mechanism in the link between epigenome dysregulation and B cell transformation. Finally, the results will likely lead to the therapeutic strategies for cancer by targeting the epigenetic machinery and/or by modulating the anti-cancer immune response.