Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia

Abstract

IntroductionB-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of a monoclonal population of CD5 ϩ neoplastic B cells in blood, secondary lymphoid tissues, and the marrow. 1 Chemokines are essential for lymphocyte trafficking and homing during immune surveillance. 2 However, the mechanisms that regulate the dissemination of CLL cells to different tissue compartments are largely unknown. Earlier, we reported that the chemokine receptor CXCR4 induces spontaneous migration of CLL cells beneath marrow stromal cells. 3 More recently, the importance of CXCR4 for homing of neoplastic B cells to the marrow was confirmed in vivo. 4 We also reported that a small proportion of monocyte-derived cells from the blood of CLL patients differentiates into large, adherent nurselike cells (NLCs) that attract CLL cells and protect them from undergoing spontaneous or druginduced cell death. [5][6][7] NLCs express high levels of CD68 and can be detected in secondary lymphoid tissues from patients with CLL. 6 NLCs therefore appear to be an integral part of the CLL microenvironment within secondary lymphoid tissues, and may be comparable with lymphoma-associated macrophages (LAMs) in follicular lymphoma. 8 The molecules involved in the cross talk between CLL cells and NLCs are only partially understood. NLCs secrete CXCL12 and thereby attract CLL cells and support their survival. 5,9 Moreover, NLCs express B-cell-activating factor of the tumor necrosis factor (TNF) family (BAFF), a proliferation-inducing ligand (APRIL), 9 CD31, and plexin-B1 10 that also protect CLL cells from apoptosis, indicating that NLCs use multiple distinct pathways to support CLL cell survival.In contrast to CXCR4, which is broadly expressed by normal and malignant hematopoietic and nonhematopoietic cells, 11 the chemokine receptor CXCR5 is expressed only by mature recirculating B cells, a small subset of CD4 ϩ and CD8 ϩ T cells, and skin-derived migratory dendritic cells (reviewed in Muller et al 12 ). CXCR5 initially was isolated from Burkitt lymphoma and designated Burkitt lymphoma receptor 1 (BLR1). 13 CXCR5 gene-deleted mice display defective formation of primary follicles and germinal centers in the spleen and Peyer patches, and lack inguinal lymph nodes. 14 Subsequently, the ligand for CXCR5 was identified and termed B-cell-attracting chemokine 1 (BCA-1). 15,16 According to our current chemokine classification, BCA-1 now is designated CXCL13. 17 CXCL13 is a homeostatic chemokine that is constitutively secreted by stromal cells in B-cell areas of secondary lymphoid tissues (follicles), where B cells encounter antigen and differentiate. Generally, CXCR5 induces recruitment of circulating naive B cells to follicles. 15,[18][19][20] Regarding the microanatomic positioning within the germinal center (GC), dark and light zones of the GC can be distinguished, and centroblasts localize to the dark zones via CXCR4. There, centroblasts rapidly divide and undergo somatic hypermutation of the antibody variable region genes. Subsequently, t...

Non-malignant B cells and chronic lymphocytic leukemia cells induce a pro-survival phenotype in CD14+ cells from peripheral blood

“…3 The spectrum of cancers with EZH2 mutation is also increasing, with mutations in myeloid disorders leading to reduced or complete loss of H3K27me3 expression consistent with a tumour suppressor role for EZH2. [4][5][6] Deregulation of the EZH2-H3K27me3 pathway may also occur by other mechanisms, with over-expression of EZH2 associated with poor outcome in a range of solid tumours. [7][8][9] In this study, we set out to determine the prevalence and the prognostic value of EZH2 Y641 variants in a large cohort of patients with FL, and the relationship between mutation and EZH2 and H3K27me3 expression.…”

“…We found that NLCs might indeed help in the survival of CLL cells in the lymph node as reported previously. 6 Interestingly, non-malignant tonsil and lymph node sections from healthy individuals were positive for these markers as well (Figures 1d and h). Although it is known that NLCs have higher CD68 intensities than macrophages and dendritic cells, immunohistochemistry is not well suited for a quantitative analysis.…”

“…5 In vivo, NLCs have been described to be present in the spleen and lymph nodes of CLL patients, suggesting that NLCs might promote survival of CLL cells also in these tissues. 5,6 Several proteins that are involved in the pro-survival capabilities of NLCs have been identified: CXCL12, 4 CXCL13, 6 BAFF (B-cell activating factor of the tumor necrosis factor family), 7 APRIL (a proliferationinducing ligand) 7 and CD31 (PECAM1). 8 NLCs have an expression profile of surface and cytoplasmic antigens that is distinct from that of other cells of the myelo-monocytic lineage.…”

Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration

“…11 Because disease progression occurs when tumor proliferation outstrips loss, the capacity of tumor cells to migrate into tissues is an important factor in determining outcome. Transit of CLL cells to the tissues is mediated, at least in part, by their expression of CD49d 12 and the chemokine receptors such as CXCR4 and CXCR5, [13][14][15] and is controlled by the secretion of the chemokine ligands including CXCL12 and CXCL13.…”

A novel role of the CX3CR1/CX3CL1 system in the cross-talk between chronic lymphocytic leukemia cells and tumor microenvironment

“…10 CLL cells overexpress CXCR5 that interacts with its ligand CXCL13 produced by CD68 þ macrophages in lymphoid tissues, thus contributing to leukemic cell migration to the latter sites. 11 Finally, migration of CLL cells to bone marrow is mediated by CXCR4, highly expressed in leukemic cells, and its ligand CXCL12, produced by stromal cells. 12 CX 3 CL1/fractalkine, a chemokine constitutively expressed by many hematopoietic and non-hematopoietic tissues, 13,14 is synthesized as membrane-bound protein but can also be released by proteolytic cleavage.…”