CCL3 (MIP-1(alpha)) plasma levels and the risk for disease progression in chronic lymphocytic leukemia

February 7, 2011

BlankBlood, 3 February 2011, Vol. 117, No. 5, pp. 1662-1669.

CCL3 (MIP-1(alpha)) plasma levels and the risk for disease progression in

chronic lymphocytic leukemia

Mariela Sivina1, Elena Hartmann2, J. Kipps3, Rassenti3,

Krupnik1, Lerner1, Ruth LaPushin1, Lianchun Xiao4, Xuelin Huang4, Lillian

Werner5, Donna Neuberg5, Hagop Kantarjian1, O'Brien1, G. Wierda1,

J. Keating1, s Rosenwald2, and Jan A. Burger1

1 Department of Leukemia, University of Texas M. D. Cancer Center,

Houston, TX; 2 Institute of Pathology, University of Würzburg, Würzburg,

Germany; 3 Chronic Lymphocytic Leukemia Research Consortium, and Division of

Hematology/Oncology, Department of Medicine, University of California San Diego,

San Diego, CA; 4 Department of Biostatistics, University of Texas M. D.

Cancer Center, Houston, TX; and 5 Department of Biostatistics and Computational

Biology, Dana-Farber Cancer Institute, Boston, MA

B-cell receptor (BCR) signaling has been inferred as an important mechanism for

disease progression in chronic lymphocytic leukemia (CLL) and other B-cell

malignancies. In response to BCR activation, CLL cells secrete the chemokine

CCL3, which fosters interactions between CLL cells and the leukemia

microenvironment. CCL3 secretion correlates with expression of the 70-kDa

(zeta)-associated protein (ZAP-70) and responsiveness of the CLL clone to BCR

stimulation. Here, we measured CCL3 plasma levels by enzyme-linked immunosorbent

assay (ELISA) in 351 CLL patients and examined CCL3 levels for associations with

established prognostic markers and time from diagnosis to initial therapy. We

found that CCL3 plasma concentrations were strongly associated with established

prognostic markers. In a proportional hazards regression model, CCL3 as well

as established prognostic markers (immunoglobulin heavy chain variable-region

mutation status, CD38 or ZAP-70 cytogenetics, clinical stage) were significantly

associated with time to treatment. Multivariable analysis revealed that CCL3

(hazard ratio

= 2.33, P < .0001), advanced clinical stage (HR = 2.75, P =

..0025), poor risk cytogenetics (del 17p, HR = 2.38; del11q, HR = 2.36, P =

..001), and CD38 expression (HR = 1.43, P = .023) were independent prognostic

markers. Collectively, CCL3 is a novel, robust, and independent prognostic

marker in CLL that can easily and reliably be measured by ELISA. CCL3 therefore

should become useful for risk assessment in patients with CLL.

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