CXCL12-induced chemotaxis is impaired in T cells from patients with ZAP-70-negative chronic lymphocytic leukemia

Abstract

The online version of the article has a supplementary appendix BackgroundT cells from patients with chronic lymphocytic leukemia may play an important role in contributing to the onset, sustenance, and exacerbation of the disease by providing survival and proliferative signals to the leukemic clone within lymph nodes and bone marrow. Design and MethodsBy performing chemotaxis assays towards CXCL12, CCL21 and CCL19, we sought to evaluate the migratory potential of T cells from chronic lymphocytic leukemia patients. We next analyzed the chemokine-induced migration of T cells, dividing the chronic lymphocytic leukemia samples according to their expression of the poor prognostic factors CD38 and ZAP-70 in leukemic cells determined by flow cytometry. ResultsWe found that T cells from patients with chronic lymphocytic leukemia are less responsive to CXCL12, CCL21 and CCL19 than T cells from healthy adults despite similar CXCR4 and CCR7 expression. Following separation of the patients into two groups according to ZAP-70 expression, we found that T cells from ZAP-70-negative samples showed significantly less migration towards CXCL12 compared to T cells from ZAP-70-positive samples and that this was not due to defective CXCR4 down-regulation, F-actin polymerization or to a lesser expression of ZAP-70, CD3, CD45, CD38 or CXCR7 on these cells. Interestingly, we found that leukemic cells from ZAP-70-negative samples seem to be responsible for the defective CXCR4 migratory response observed in their T cells. ConclusionsImpaired migration towards CXCL12 may reduce the access of T cells from ZAP-70-negative patients to lymphoid organs, creating a less favorable microenvironment for leukemic cell survival and proliferation.Key words: chronic lymphocytic leukemia, T-cell chemotaxis, CXCL12, CXCR4. ZAP-70-negative chronic lymphocytic leukemia. Haematologica 2010;95:768-775. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Citation: Borge M, Nannini PR, Galletti JG, Morande PE, Ávalos JS, Bezares RF, Giordano M, and Gamberale R. CXCL12-induced chemotaxis is impaired in T cells from patients with CXCL12-induced chemotaxis is impaired in T cells from patients with ZAP-70-negative chronic lymphocytic leukemia

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“…It is still unclear if CXCR7 is expressed at all on any class of leukocyte in adult mammals [43,44]. Accordingly, some debate still exists as to whether or not CXCR7 primarily acts as a decoy (non-signaling) receptor [45,46].…”

“…CXCR7 (also known as receptor dog cDNA 1; RDC1) is a more recently discovered chemokine receptor that also preferentially binds CXCL12 [ 42 ]. It is still unclear if CXCR7 is expressed at all on any class of leukocyte in adult mammals [ 43 , 44 ]. Accordingly, some debate still exists as to whether or not CXCR7 primarily acts as a decoy (non-signaling) receptor [ 45 , 46 ].…”

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“…Cells were used immediately or were cryopreserved in FCS 20% DMSO for further experiments. B cells (CD19 + ) were purified by negative selection using mouse mAbs specific for CD14, CD56, CD3, or CD2 and magnetic beads, as described previously (30). The purity of B cells was checked using a FACS flow cytometer (BD Immunocytometry Systems) and anti-CD19 MoAb and was always .98%.…”

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“…If it is the case, LPL might also act as a crosstalk factor facilitating specific interactions with accessory cells in tissue microenvironments. LPL might then be added to the list of proteins implicated in the activation of CLL proliferative pool together with integrins such as CD49d, metalloproteinases (MMP-9), antiapoptotic molecules (BCL2) as well as chemokines (CCL3, CCL4, CXCL12) [ 68 , 69 ]. Thus, LPL could be contributing to leukemic progression either per se through metabolic reprogramming, or through the synergistic contribution to an activating microenvironment in which the leukemic clone is continuously nourished ( Figure 1 ).…”