Mechanism of GCs and BCR signaling inhibitors in CLL. (A) GCs inhibit transcription-dependent and -independent lymphocyte activation. Related to lymphocyte redistribution, GCs can up-regulate CXCR4 expression and signaling in normal T cells, thereby enhancing T-cell homing to the marrow. The mechanism of lymphocyte redistribution in CLL is currently unknown, but likely also is attributable to interference with homing mechanism. Besides effects on lymphocyte migration and homing, GCs bind to GCR in the cytosol, displacing heat-shock protein 90. GC-GCR complexes move into the nucleus, where they interfere with transcription. They also initiate transcription and translation of proteins, for example, of inhibitor of NF-κB (IκB). IκB then sequesters NF-κB. In addition, GC-GCR complexes can directly interact with NF-κB to suppress cytokine production. How these GCs mechanisms apply to CLL survival and proliferation is currently unknown. (B) Molecular interactions between CLL and stromal cells in the marrow and/or lymphoid tissue microenvironments and how these relate to BCR signaling and BCR-associated kinases (SYK, BTK, PI3K, modified after Figure 2 in Burger et al² ). BCR-associated kinases can influence CLL cell survival and proliferation (left) and CLL cell homing and retention in the tissues (right). Contact between CLL cells and NLC or mesenchymal stromal cells (MSC) is established and maintained by chemokine receptors and adhesion molecules expressed on CLL cells. 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 co-operate with chemokine receptors in establishing cell-cell adhesion through respective ligands on the stromal cells (VCAM-1 and fibronectin/FN). SYK, BTK, and PI3Ks are involved in chemokine receptor and adhesion molecule signaling in normal B cells⁸⁹  and CLL cells.¹⁸  The clinical responses to small molecule antagonists to each of these kinases are characterized by “mobilization” of tissue-resident CLL cells into the blood, which indicates an important role of these kinases for CLL tissue homing and retention, as indicated in the diagram. Self and/or environmental antigens are considered a key factor in activation and expansion of the CLL clone. The nature and source of antigens and its mode of presentation to CLL cells are largely unknown. Stimulation of the BCR complex (BCR and CD79a,b) induces downstream signaling by recruitment and activation of SYK, BTK, and PI3Ks. Finally, BCR activation causes CLL cells to secrete high levels of the chemokines CCL3 and CCL4, which are potent T-cell attractants.