Down-regulation of CXCR4 and CD62L in Chronic Lymphocytic Leukemia Cells Is Triggered by B-Cell Receptor Ligation and Associated with Progressive Disease

Abstract

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 BCRdependent 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. [Cancer Res 2009;69(16):6387-95]

Prognosis of Binet stage A chronic lymphocytic leukemia patients: the strength of routine parameters

“…19 The prominence of factors related to proliferation is in line with the key role of BCR signaling capacity and microenvironment in disease progression. 6,20 As the 4 prognostic factors had independent prognostic weight, we combined these unfavorable factors. The cohort was split into 5 groups according to the number of unfavorable prognostic factors they exhibited.…”

Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia

“…26 These in vivo data indicate that CLL subclones with lower blood CXCR4 surface levels are a fraction of cells that has recently exited the tissues into the blood. BCR signaling results in the down-modulation of CXCR4, 17,27 along with enhanced chemotaxis toward CXCL12 and CXCL13. 17 This may explain why ZAP-70 ϩ CLL cells display increased chemotaxis and survival in response to CXCL12 compared with ZAP-70 Ϫ CLL cells, 28 given that ZAP-70 expression is associated with a higher responsiveness to BCR stimulation.…”

The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia

“…Interestingly, several CLL cells evade apoptosis in vitro through an enhanced survival response after BCR stimulation. 6,7,9,10 After BCR triggering, which is mediated by antigen binding to cell surface Igs, prolonged activation of the MEK-ERK and PI3K-AKT pathways, as well as efficient degradation of I]kappa]B and activation of NF-B have been associated with the induction of antiapoptotic and survival signals. [11][12][13] These molecular events lead to important changes in gene transcription and subsequent B-cell fate specification.…”

“…Considerable amounts of data have shown that antigen-driven signals are involved in the pathogenesis and progression of CLL malignancies. [6][7][8][9] Although CLL cells accumulate and are resistant to cell death in vivo, they rapidly become apoptotic during in vitro culture. Interestingly, several CLL cells evade apoptosis in vitro through an enhanced survival response after BCR stimulation.…”