DNA methylation is the best-studied epigenomic modification up to date, which is a key mechanism for transcriptional regulation. DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repressing of transposable elements, aging and carcinogenesis. It is crucial to understand the establishment /maintenance of DNA methylation and the important roles that DNA methylation dysfunction played in cellular development and tumorigenesis. Using TET1, TET2 and TET3 triple-knock-out (TKO) human embryonic stem cells (hESCs), we found that TET proteins safeguard bivalent promoters from de novo methylation to ensure robust lineage-specific transcription upon differentiation. Moreover, we designed a comprehensive computational methodology to thoroughly analyze DNA methylation patterns during tumor evolution based on bisulfite converted sequencing data. Utilizing this pipeline, we show that patients exhibit heterogeneous evolution of tumor methylomes during relapse in diffuse large B-cell lymphomas (DLBCL). Also, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse.