Molecular interactions in the CLL microenvironment. Molecular interactions between CLL and stromal cells in the BM and/or lymphoid tissue microenvironments that are considered important for CLL-cell survival and proliferation, CLL-cell homing, and tissue retention. Contact between CLL cells and NLCs or BMSCs is established and maintained by chemokine receptors and adhesion molecules expressed on CLL cells. NLCs express the chemokines CXCL12 and CXCL13, whereas BMSCs predominantly express CXCL12. The chemokine receptors CXCR3 and CCR7 are additional chemokine receptors on CLL cells that are involved in lymphatic tissue homing. NLCs and BMSCs attract CLL cells via the G protein–coupled chemokine receptors CXCR4 and CXCR5, which are expressed at high levels on CLL cells. Integrins, particularly VLA-4 integrins (CD49d), expressed on the surface of CLL cells cooperate with chemokine receptors in establishing cell-cell adhesion through respective ligands on the stromal cells (VCAM-1 and fibronectin). NLCs also express the TNF family members BAFF and APRIL, providing survival signals to CLL cells via corresponding receptors (BCMA, TACI, and BAFF-R). CD38 expression allows CLL cells to interact with CD31, the ligand for CD38 that is expressed by stromal and NLCs. Ligation of CD38 activates ZAP-70 and downstream survival pathways. Self- and/or environmental Ags are considered key factors in the activation and expansion of the CLL clone by activation of the BCR and its downstream kinases. Stimulation of the BCR complex (BCR and CD79a,b) induces downstream signaling by recruitment and activation of Syk, Btk, and PI3Ks. Finally, BCR stimulation and coculture with NLCs also induces CLL cells to secrete chemokines (CCL3, CCL4, and CCL22) for the recruitment of immune cells (T cells and monocytes) for cognate interactions. CD40L⁺ (CD154⁺) T cells are preferentially found in CLL-proliferation centers,³⁸  and can interact with CLL cells via CD40. (Modified with permission from Burger et al.¹ )