Clinical significance of chemokine receptor (CCR1, CCR2 and CXCR4) expression in human myeloma cells: the association with disease activity and survival.
OBJECTIVE
The capacity of multiple myeloma (MM) cells to home to and reside in the bone marrow implies that they must be equipped with appropriate adhesion molecules and chemokine receptors to allow transendothelial migration. We and others have previously shown that human MM cells express at least three different chemokine receptors that are functionally involved in MM cell migration, i.e. CCR1, CCR2 and CXCR4. In this study, we analyzed the surface expression of these chemokine receptors on primary MM cells from bone marrow samples.


METHODS
Chemokine receptor expression was analyzed on bone marrow samples from a large population of patients (n=80) by flow cytometric analysis. The chemokine receptor expression profile was compared with clinical characteristics. Statistical significance was evaluated by Fisher's exact test. Survival curves were constructed using the Kaplan-Meier method. Cox regression analysis was used to determine the effect of chemokine receptor expression on survival.


RESULTS
A heterogeneous expression pattern was observed for the three receptors tested. The chemokine receptor status (CRS) (i.e. no expression versus expression of at least one chemokine receptor), as well as expression of individual chemokine receptors was analyzed in relation to clinical and laboratory features and evaluated for prognostic significance. Chemokine receptor expression was significantly inversely correlated with disease activity: patients with active disease showed a significantly lower expression of CCR1, CCR2, as well as CXCR4 as compared to patients with non-active disease. Furthermore, the chemokine receptor expression profile correlated with serum beta2-microglobulin, C-reactive protein and hemoglobin. CRS, and the individual expressions of CCR1, CCR2 and CXCR4 in diagnostic bone marrow samples (n=70) correlated with survival. Multivariate analysis, using the Cox proportional hazard regression model, identified CRS, along with serum beta-microglobulin, as an independent prognostic factor.


CONCLUSIONS
This study indicates that the chemokine receptor expression profile of MM cells correlates with disease status and survival of MM patients. This observation might reflect impaired chemoattraction and retention of MM cells within the bone marrow microenvironment, resulting in disease progression.
Vande Broek
Isabelle
I
Department Hematology-Immunology, Vrije Universiteit Brussel, aarbeeklaan 101, 1090 Brussels, Belgium.
Van de Broek
Isabelle
I
Leleu
Xavier
X
Schots
Rik
R
Facon
Thiery
T
Vanderkerken
Karin
K
Van Camp
Ben
B
Van Riet
Ivan
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000401:mortality / Q000473:pathology*; D009363:Neoplasm Proteins / Q000032:analysis; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019718:Receptors, CXCR4 / Q000235:genetics; D019707:Receptors, Chemokine / Q000032:analysis*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
C515300:CCR1 protein, human; C515334:CCR2 protein, human; D009363:Neoplasm Proteins; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine