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

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BlankHaematologica, Vol 95, Issue 5, 768-775 doi:10.3324/haematol.2009.013995

CXCL12-induced chemotaxis is impaired in T cells from patients with

ZAP-70-negative chronic lymphocytic leukemia

Mercedes Borge1, a Romina Nannini1, Jeremías Gastón Galletti1, Pablo Elías

Morande1, Julio Sánchez Ávalos2, Raimundo Bezares3, Mirta Giordano1,4,

Romina Gamberale1,4

1 Laboratorio de Inmunología Oncológica, IIHema, Academia Nacional de Medicina

2 Instituto Fleming, Ciudad de Buenos Aires

3 Hospital General de Agudos Dr. T. Álvarez, Ciudad de Buenos Aires and

4 Departamento de Microbiología Parasitología e Inmunología, Facultad de

Medicina, Universidad de Buenos Aires, Argentina

Correspondence: Romina Gamberale, Laboratorio de Inmunología, Oncológica,

Academia Nacional, de Medicina, Pacheco de Melo, 3081 (1425) Ciudad de, Buenos

Aires, Argentina. E-mail: rominagamberale@...

Background: T 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 Methods: By 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.

Results: We 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.

Conclusions: Impaired 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.