Down-regulation of CXCR4 and CD62L in chronic lymphocytic leukemia cells is triggered by B-cell receptor ligation and associated with progressive disease.
Progressive cases of B-cell chronic lymphocytic leukemia (CLL) are frequently associated with lymphadenopathy, highlighting a critical role for signals emanating from the tumor environment in the accumulation of malignant B cells. We investigated on CLL cells from 30 untreated patients the consequence of B-cell receptor (BCR) triggering on the membrane expression of CXCR4 and CD62L, two surface molecules involved in trafficking and exit of B-lymphocytes from lymph nodes. BCR stimulation promoted a strictly simultaneous down-regulation of CXCR4 and CD62L membrane expression to a variable extent. The variable BCR-dependent decrease of the two proteins was strikingly representative of the heterogeneous capacity of the CLL cells to respond to BCR engagement in a given patient. Functionally, cells down-regulating CXCR4 and CD62L in response to BCR engagement displayed a reduction in both migration toward CXCL12 and adhesion to lymphatic endothelial cells. Remarkably, the ability of CLL cells to respond to BCR ligation was correlated with unfavorable prognostic markers and short progression-free survival. In conclusion, BCR signaling promotes decrease of CXCR4 and CD62L membrane expression in progressive cases only. These results are consistent with the hypothesis that BCR-mediated signaling pathways favor accumulation of a proliferative pool within the lymph nodes of progressive CLL cases.
Vlad
Amalia
A
UMR U978 Institut National de la Santé et de la Recherche Médicale-Université Paris 13, UFR SMBH and AP-HP, Service d'hématologie biologique, Hôpital Avicenne, Bobigny, France.
Deglesne
Pierre-Antoine
PA
Letestu
Rémi
R
Saint-Georges
Stéphane
S
Chevallier
Nathalie
N
Baran-Marszak
Fanny
F
Varin-Blank
Nadine
N
Ajchenbaum-Cymbalista
Florence
F
Ledoux
Dominique
D
D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019041:L-Selectin / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008024:Ligands; D009362:Neoplasm Metastasis; D011379:Prognosis; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D000888:Antibodies, Anti-Idiotypic; C527276:CXCR4 protein, human; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D019718:Receptors, CXCR4; C044203:anti-IgM; D019041:L-Selectin