Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas

Abstract

IntroductionChemokines represent a group of molecules that regulate cell migration and can be distinguished in inflammatory and homeostatic chemokines. These latter are involved in the homeostasis of the immune system. [1][2][3][4][5][6][7][8] Cells are exposed to a complex pattern of chemoattractant signals that, through a gradient of chemokine concentrations, drive the migration of lymphocytes to target tissues or lymphoid organs. Different chemokine receptors are able to bind the same chemokine and, in turn, different chemokines are able to bind the same receptor, indicating that redundancy is a definite feature of the chemokine network. Chemokine-receptor interactions are of crucial importance for homeostatic functions within the immune system, particularly for establishing the complex architecture of the secondary lymphoid organs. 3,4,9 The role of chemokines for B-cell lymphopoiesis has been primarily demonstrated for CXCL12 (stromal-derived factor 1␣ ) and its receptor CXCR4. 10 CXCL12 can induce chemotaxis of B-cell progenitors, indicating that the CXCL12/ CXCR4 system may be important in directing the migration of B-cell progenitors to the appropriate bone marrow microenvironment. [11][12][13] In addition, it is highly expressed on B lymphocytes and it is likely to play a key role in the architecture of spleen and lymph nodes. To date, most information in terms of chemokines and their receptors has been provided on normal human B cells and in the mouse; little data are available on the role of these molecules on malignant B lymphocytes. [14][15][16][17] In particular, it has been demonstrated that malignant B cells express CXCR3 in different neoplastic conditions and mediate migration following the binding of the chemokines CXCL10 (inflammatory protein 10 [IP-10]) and CXCL9 (Mig). 14,16 Furthermore, CXCR4, a receptor constitutively expressed on normal B lymphocytes, has been detected on malignant B lymphocytes from patients with chronic lymphocytic leukemia (CLL). 15 In this study, we investigated the expression and functional role of a large spectrum of chemokine receptors, including CCR1 to CCR6 and CXCR1 to CXCR5, in several B-cell non-Hodgkin lymphomas (NHLs). We demonstrated that these receptors recognize different B-cell malignancies and mediate chemotaxis following binding to their own ligands. Patients, materials, and methods Patient samplesForty-three patients with different B-cell malignancies were studied at the time of diagnosis. 18 This study was approved by the Università of Padova institutional review board. Informed consent was provided according to the Declaration of Helsinki. Thirteen patients (10 men and 3 women, ages 46-78 years) with the diagnosis of B-CLL were graded according to the Rai staging system 19 Preparation of cell suspensionsPeripheral blood mononuclear cells (PBMCs) from patients with NHL were obtained from freshly heparinized blood samples by centrifugation on Ficoll/Hypaque (F/H) gradient. 20 Normal B lymphocytes were obtained from 5 tonsils after mechanic disruption...

Recurrent loss of the Y chromosome and homozygous deletions within the pseudoautosomal region 1: association with male predominance in mantle cell lymphoma

“…10,11 Future studies, including mutation and expression analyses of genes located in PAR1, might lead to the identification of candidate genes involved in MCL lymphomagenesis. …”

PIM Kinases Are Essential for Chronic Lymphocytic Leukemia Cell Survival (PIM2/3) and CXCR4-Mediated Microenvironmental Interactions (PIM1)

“…18). CXCR4 activation by CXCL12 gradients induces CLL cell chemotaxis, migration across the vascular endothelium, actin polymerization, and migration under or underneath BMSCs and also shows direct antiapoptotic effects (12,19,20). Binding of CXCL12 to the CXCR4 receptor results in an internalization of the CXCR4 receptor by receptor endocytosis and pathway activation including extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) cascade activation and intracellular calcium flux (12).…”

Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma

“…2 Further, different patterns of chemokine receptor expression identified in different malignant B-cell subsets suggest that these chemokine receptors are functional and have a crucial role in malignant B-cell circulation leading to the emergence of monoclonal B cells and, eventually to transformation. [8][9][10][11] The development of chemokine antagonists and their use in clinical trials for a variety of diseases shows the potential of chemokine receptors for molecular-targeted therapy. 12 The aim of the present study was to identify expression patterns of 19 chemokine receptors of non-neoplastic stomach specimens, H. pyloriassociated gastritis, gastric MALT lymphomas and of extranodal diffuse large B-cell lymphoma arising from MALT lymphoma (transformed MALT lymphoma) in the stomach.…”