Early stages in the development of chronic lymphocytic leukemia (CLL) have not been explored mainly due to the inability to study normal B-cells en route to transformation. In order to determine such early events of leukemogenesis, we have used a well established mouse model for CLL. Over-expression of human TCL1, a known CLL oncogene in murine B-cells leads to the development of mature CD19+/CD5+/IgM+ clonal leukemia with a disease phenotype similar to that seen in human CLL. Herein, we review our recent study using this TCL1-driven mouse model for CLL and corresponding human CLL samples in a cross-species epigenomics approach to address the timing and relevance of epigenetic events occurring during leukemogenesis. We demonstrated that the mouse model recapitulates the epigenetic events that have been reported for human CLL, affirming the power and validity of this mouse model to study early epigenetic events in cancer progression. Epigenetic alterations are detected as early as three months after birth, far before disease manifests at about 11 months of age. These mice undergo NFkB repressor complex mediated inactivation of the transcription factor Foxd3, whose targets become aberrantly methylated and silenced in mouse and human CLL. Overall, our data suggest the accumulated epigenetic alterations during CLL pathogenesis as a consequence of gene silencing through TCL1 and NFkB repressor complex, suggesting the relevance for NFκB as a therapeutic target in CLL.