Three models of lymphoma ontogeny. In the first model (left), a normal lymphocyte acquires the full complement of alterations at a single stage of maturation that corresponds to the lymphoma phenotype. In the second model (center), 1 or more initiating events occur during early lymphoid maturation and the remaining alterations develop at a stage corresponding to the lymphoma phenotype. In the third model (right), the initial alterations are acquired within hematopoietic stem cells that acquire additional alterations at multiple stages of differentiation. At some stages, the cells have self-renewal capacity (indicated by semicircular arrows) that promotes further clonal heterogeneity, as indicated by cells of multiple colors. MPP indicates multipotent progenitor; and CLP, common lymphoid progenitor.