Enhanced Chemokine Receptor Recycling and Impaired S1P1 Expression Promote Leukemic Cell Infiltration of Lymph Nodes in Chronic Lymphocytic Leukemia.
Lymphocyte trafficking is orchestrated by chemokine and sphingosine 1-phosphate (S1P) receptors that enable homing and egress from secondary lymphoid organs (SLO). These receptors undergo rapid internalization and plasma membrane recycling to calibrate cellular responses to local chemoattractants. Circulating chronic lymphocytic leukemia (CLL) cells display an abnormal increase in the surface levels of the homing receptors CCR7 and CXCR4 concomitant with low S1P receptor 1 (S1P1) expression. In this study, we investigated the role of receptor recycling on CXCR4/CCR7 surface levels in CLL cells and addressed the impact of quantitative alterations of these receptors and S1P1 on the ability of leukemic cells to accumulate in SLOs. We show that recycling accounts, to a major extent, for the high levels of surface CXCR4/CCR7 on CLL cells. In addition, increased expression of these receptors, together with S1P1 deficiency, is detectable not only in circulating leukemic cells, but also in SLOs of CLL patients with lymphoadenopathy. We further provide evidence that ibrutinib, a Btk inhibitor that promotes mobilization of leukemic cells from SLOs, normalizes the imbalance between CXCR4/CCR7 and S1P1. Taken together, our results highlight the relevance of chemokine and S1P receptor recycling in CLL pathogenesis and clinical outcome.
Department of Life Sciences, University of Siena, Siena, Italy. Istituto Toscano Tumori, Siena, Italy.
Laura
L
Patrussi
Department of Life Sciences, University of Siena, Siena, Italy. Istituto Toscano Tumori, Siena, Italy.
Nagaja
N
Capitani
Venetian Institute of Molecular Medicine, Padua, Italy. Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
Veronica
V
Martini
Surgical Pathology and Cytopathology Unit, Department of Medicine, University of Padua, Padua, Italy.
Marco
M
Pizzi
Venetian Institute of Molecular Medicine, Padua, Italy. Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
Valentina
V
Trimarco
Venetian Institute of Molecular Medicine, Padua, Italy. Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
Federica
F
Frezzato
Surgical Pathology and Cytopathology Unit, Department of Medicine, University of Padua, Padua, Italy.
Filippo
F
Marino
Venetian Institute of Molecular Medicine, Padua, Italy. Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
Gianpietro
G
Semenzato
Venetian Institute of Molecular Medicine, Padua, Italy. Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
Livio
L
Trentin
Department of Life Sciences, University of Siena, Siena, Italy. Istituto Toscano Tumori, Siena, Italy. baldari@unisi.it.
Cosima T
CT
Baldari
D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002633:Chemotaxis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism*; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D017254:Leukemic Infiltration / Q000503:physiopathology*; D008198:Lymph Nodes / Q000473:pathology*; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors
C515370:CCR7 protein, human; C527276:CXCR4 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D016201:Receptors, Lymphocyte Homing; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors