Cellular interactions. (A) Marrow and (B) lymphatic tissue microenvironments in mature B-cell tumors. (A) MSCs (arrow), also called reticular cells, are scattered throughout the marrow cavity and constitutively secrete high levels of the chemokine CXCL12 (SDF-1). MSCs colocalize with the vasculature, forming so-called “vascular niches.” CXCL12 secretion by MSC induces CXCL12 gradients that can attract circulating neoplastic B cells via CXCR4 receptors expressed on CLLs, MM, and other malignant B cells. Circulating lymphoma cells may become attracted by CXCL12 gradients to home to the marrow where contact with MSCs provides them with growth and survival signals. Mesenchymal-derived osteoblasts are specialized fibroblasts critical for bone formation and able to secrete CXCL12. Therefore, interaction with osteoblasts is an alternative, additional niche where lymphoma cells can home. These cellular interactions also confer drug resistance to leukemia/lymphoma cells and may therefore account for MRD. (B) In secondary lymphoid tissues, CLL cells and other lymphoma cells can interact with a variety of accessory cells, such as MSCs, monocyte-derived NLCs, which are similar to LAMs, and T cells. The presence of FDCs in lymphoid tissues in CLL is controversial. Formation of proliferation centers is a hallmark of CLL histopathology. Interactions between CLL and accessory cells within proliferation centers are critical for providing growth and survival signals to CLL B cells, inducing their proliferation and resembling interactions between normal, antigen-stimulated B cells and accessory cells (antigen-presenting cells, T cells) during GC reaction. CLL cells outside the proliferation centers are resting and considered the nonproliferative compartment.