Hypothetical model of the lifecycle of a CLL B cell. Part 1: CLL cells rest on the stroma because of at least CXCR4-CXCL12 interactions. When stimulated, cells are activated and divide, upregulating CD5, internalizing CXCR4 and detaching from stroma. The process could be ligand-induced (for example, BCR or toll-like (TLR) or other pathways) or spontaneous. Low CXCR4 levels increase the chances of recently divided CLL cells (CXCR4dimCD5bright phenotype) exiting solid tissue and reaching peripheral blood. Part 2: Recently born/divided CLL cells reach peripheral blood as members of the CXCR4dimCD5bright fraction. Over time, possibly because of a lack of trophic input from the solid tissue microenvironment, cells begin to reexpress CXCR4 to trek back to nutrient-rich niches. This leads to expression of a CXCR4intCD5int and then CXCR4brightCD5dim membrane phenotype. The model considers the three fractions to be linked as a continuum. Part 3: CXCR4brightCD5dim CLL cells have the greatest chance of detecting and following a CXCL12/SDF1 gradient, thereby reentering lymphoid solid tissue and receiving prosurvival stimuli. Those that do not reenter die by exhaustion.