Structure and function of the hematopoietic cancer niche: focus on chronic lymphocytic leukemia

Abstract

Chronic Lymphocytic Leukemia (CLL) is a B cell malignancy characterized by the accumulation of mature monoclonal CD5-positive B cells in the blood, secondary lymphoid tissues, and marrow. The infiltration of CLL cells in lymphoid tissues is a key element of disease pathogenesis. It is in such tissues that are found the microenvironments that provide CLL cells protection from spontaneous and/or drug-induced apoptosis. CLL cells actively shape their microenvironment by producing cytokines and chemokines, and by subverting normal accessory cells to promote leukemia-cell survival, proliferation, and escape from immune detection. In this review, we discuss how CLL cells disrupt the niches required for normal hematopoiesis or immune function and subvert normal cells in the microenvironment to support neoplastic cell growth and survival.

Figure 1

CLL microenvironment: the supportive cells and factors. CLL cells are recruited into the marrow and secondary lymphoid tissues following chemokine gradients. The migration of CLL cells into the marrow is primarily mediated through CXCR4 in response to CXCL12 (3), which is secreted mainly by NLCs (42) and MSCs (86, 87). CLL cells also are attracted to lymph nodes via CCR7 in response to the chemokines CCL19 and CCL21, which are produced by High Endothelial Venules (HEV) (22). The basement membranes of HEV also express hyaluronan (HA), which can interact with CD44, a signaling glycosoaminoglycan expressed by CLL cells that can recruit membrane-associated receptor-tyrosine kinases or their substrates and thereby facilitate cell signaling (–120). It also might enhance the production of active MMP-9 (25), which could facilitate entry through the marrow. Follicular dendritic cells (FDCs), on the other hand, can secrete CXCL13 (94), which can attract CLL cells via CXCR5. Once in tissues, CLL cells can derive survival support from the same chemokines, as well as from additional factors elaborated by accessory cells in the CLL microenvironment. For instance, CLL cells come in contact with NLCs that can promote CLL cell survival through the production of CXCL12 (42). NLCs also express BAFF (B cell activating factor of the TNF family) and APRIL (a proliferation-inducing ligand), which can complement the survival stimulus afforded by CXCL12 (44). NLC-CLL interactions also can promote CLL-cell survival through cognate interactions between CD31 and CD38, which are expressed on NLC and CLL cells, respectively (80). In turn, CLL cells may secrete chemokines, such as CCL3 and CCL4 (81), which can recruit T cells and NLC-precursor cells to the CLL niche. T cells in that microenvironment might become activated and provide CLL cells with proliferative signals through CD154-CD40 interactions (30), as well as through the secretion of multiple cytokines, such as IL-2, IL-4, and IL-10 (92). In return, activated CLL cells secrete CCL12 and CCL22 (30, 93), chemokines that can attract more CCR4⁺ T cells into the CLL niche. MSCs also can contribute to CLL cell survival via the secretion of CXCL12, and in contrast to NLCs, also via the production of Wnt5a (Wingless-type MMTV integration site family, member 5a) (121), which can interact with ROR1 (Receptor tyrosine kinase-like Orphan Receptor 1) expressed by CLL cells (90). CLL-MSC contact also can be established through VCAM-1–CD49d interactions that contribute to CLL-cell survival (122). In tissues, CLL cells can be exposed to environmental and/or self antigens that might trigger cell activation through interactions with the surface immunoglobulin (sIg) expressed by CLL cells. Stimulation from ligation of sIg with antigen could amplify the responsiveness of CLL cells to the signals and factors provided by the CLL microenvironment.