Relationship of epigenetic alterations in normal B-cell and tumor development. Substantial genome-wide epigenetic modification occurs in sequential normal B-cell subpopulations, creating a continuum of epigenetic states involving targeted modification of promoters and enhancers, as well as global changes. Transforming event(s) (genetic, epigenetic, and/or others) are associated with alteration of the epigenetic state occur in a founder cell. The resulting tumor epigenetic pattern is a composite of the original B-cell and tumor-specific events. Subtypes of the same B-cell malignancy may derive from different stages of normal B-cell differentiation, as documented in MCL¹³  and CLL.^9,10  Tumors exhibit an accelerated degree of differentiation relative to inferred normal cell of origin (including substantial global DNA methylation loss), permanently obscuring knowledge of the precise original phenotype. MCL-C1 and -C2, mantle cell lymphoma cluster 1 and 2, respectively; LP- and HP-CLL, low- and high-programmed CLL, respectively; ncsMBC and csMBC, non-class-switched and class-switched memory B cells, respectively.