The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes.
Malignant lymphocyte migration into lymph nodes is an important aspect of chronic lymphocytic leukemia (CLL), yet little is known about the processes involved. Here we demonstrate that CLL cells migrate across vascular endothelium in response to at least 3 chemokines, namely, CCL21, CCL19, and CXCL12. Moreover, transendothelial cell migration (TEM) in response to CCL21 and CCL19 was significantly higher for the malignant B cells of patients who had clinical lymph node involvement as compared with those of patients lacking such organomegaly. Furthermore, the expression of CCR7, the receptor for both CCL21 and CCL19, correlated with clinical lymphadenopathy, and blocking of CCR7 inhibited CLL cell TEM. By using immunohistochemistry we demonstrated that CCL21 and CCL19, but not CXCL12, are located in high endothelial venules and are, therefore, in an appropriate location to induce TEM. Regarding the adhesion receptors involved in TEM, alpha4 (most likely in association with beta1) and alphaLbeta2 were shown to be important in CLL cell TEM in vitro, but only the level of alpha4 expression correlated with the presence of clinical lymphadenopathy. The present studies are the first to shed light on the factors determining CLL cell entry into nodes and define the phenotype of circulating malignant cells likely to determine the pattern of lymph node enlargement in the disease.
Till
Kathleen J
KJ
Department of Haematology, University of Liverpool, Liverpool, United Kingdom. k.j.till@liv.ac.uk
Lin
Ke
K
Zuzel
Mirko
M
Cawley
John C
JC
D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000378:metabolism / Q000502:physiology; D002633:Chemotaxis; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D006801:Humans; D039441:Integrin alpha4; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology*; D008206:Lymphatic Diseases / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology
D015703:Antigens, CD; C515460:CCL19 protein, human; C515478:CCL21 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D008024:Ligands; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D039441:Integrin alpha4