CLL cell trafficking and tissue homing. CLL cells circulate in the peripheral blood, where they become attracted into the lymph nodes and bone marrow by chemokine gradients established by tissue stromal cells. Critical chemokines for lymph node homing are CXCL12, CXCL13, and CCL19/21, which bind to CXCR4, CXCR5, and CCR7 chemokine receptors on CLL cells, respectively. The CXCR4-CXCL12 axis is the predominant factor for marrow homing, and CXCL12 tissue expression is regulated by oxygen tension, as indicated by the triangles. Expression levels of CXCR4 on blood CLL cells can be used to distinguish CLL cells that are on their way into the tissues (CXCR4 high) versus CLL cells that recently have exited the tissues (CXCR4 dim). CLL adhesion molecules (integrins, selectins, CD44) co-operate with chemokine receptors during tissue homing. Pharmacologic inhibition of these homing mechanisms interferes with 2 distinct events: first, it leads to exit of tissue CLL cells into the blood, causing an increase in lymphocytosis. Second, this also causes inhibition of recirculation of blood CLL cells into the tissues.