Molecular crosstalk between malignant B cells, exemplified for CLL B cells, and the microenvironment. This figure displays the molecules involved in crosstalk between CLL cells and accessory cells in the marrow and/or lymphoid tissue microenvironments. Contact between CLL cells (and various other mature B-cell lymphomas, as detailed in the text) and NLCs/LAMs or MSCs is established and maintained by chemokine receptors and adhesion molecules. NLCs express the chemokines CXCL12 and CXCL13, whereas MSCs predominantly express CXCL12. NLCs and MSCs 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/FN). NLCs also express the TNF family members BAFF and a proliferation-inducing ligand, providing survival signals to CLL cells via corresponding receptors (BCMA, TACI, BAFF-R). CD38 expression allows CLL cells to interact with CD31, the ligand for CD38, expressed by stromal and NLCs. Ligation of CD38 activates ZAP-70 and downstream survival pathways. Self and/or environmental antigens (Ag) are considered a key factor in stimulation and expansion of the CLL clone. The nature and source of Ag and its mode of presentation in CLLs are unknown and currently the focus of intensive research. Stimulation of the BCR complex (BCR and CD79a,b) induces downstream signaling by recruitment and activation of Syk and ZAP-70. BCR stimulation and coculture with NLCs also induce CLL cells to secrete high levels of the chemokines CCL3 and CCL4, which are potent T cell–attracting chemokines. Through this mechanism, CLL cells can actively recruit T cells for cognate T-cell interactions with CLL cells. CD40L⁺ T cells are preferentially found in CLL proliferation centers and can interact with CLL cells via CD40. Cytokines secreted by T cells or CLL cells, such as IL-4, or TNF-α are considered important regulators of CLL cell survival. Hedgehog (Hh) proteins, such as the indian (Ihh) and sonic (Shh) hedgehog proteins, are stromal cell–derived factors that can regulate survival of CLL and other mature B-cell malignancies.⁵⁴  ROR1, an oncofetal antigen with CLL-restricted expression, may function as receptor for Wnt5a,⁵⁵  expressed by stromal cells. Collectively, this crosstalk between CLL cells and accessory cells results in activation of survival and drug resistance pathways, such as those provided by Bcl-2 and Mcl-1.