title: High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia.
abstract: Childhood acute lymphoblastic leukaemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. Such extramedullary presentation is important for understanding the biology of childhood ALL and also for developing new prognostic parameters. A potential mechanism in the trafficking of leukaemia cells is the interaction of the chemokine receptor CXCR4, which is expressed on ALL cells, and its ligand stromal cell-derived factor-1 (SDF-1), produced by stromal cells in bone marrow and extramedullary organs. Functionality of CXCR4 was demonstrated by a high correlation between cell surface density of CXCR4 and transendothelial migration of leukaemia blasts towards a gradient of SDF-1 (r = 0.73, P = 0.001). Inhibition of SDF-1-induced migration by an anti-CXCR4 monoclonal antibody (78.33 +/- 23.86% inhibition) evidenced the specificity of CXCR4 to SDF-1. In order to evaluate clinical significance of CXCR4 expression, lymphoblasts from the bone marrow of 73 patients with and without extramedullary organ infiltration were compared. Multiparameter flow cytometry revealed that lymphoblasts from patients with high extramedullary organ infiltration, defined as ultrasonographically measured enlargement of liver or spleen, expressed the CXCR4 receptor at higher fluorescence intensity (median 66.12 +/- 66.17) than patients without extramedullary organ infiltration (median 17.56 +/- 19.29; P < 0.001). Consequently, high expression of CXCR4 was strongly predictive for extramedullary organ involvement, independently of the peripheral lymphoblast count. Highest CXCR4 expression was seen in mature B ALL (median 102.74 +/- 92.13; P < 0.003), a disease characterized by a high incidence of extramedullary bulky disease. As high expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood ALL, we suggest that CXCR4 and its ligand play an essential role in extramedullary invasion.
authors.affiliation: Department of Paediatrics, University of Innsbruck, Innsbruck, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Crazzolara
authors.forename: A
authors.initials: A
authors.lastname: Kreczy
authors.forename: G
authors.initials: G
authors.lastname: Mann
authors.forename: A
authors.initials: A
authors.lastname: Heitger
authors.forename: G
authors.initials: G
authors.lastname: Eibl
authors.forename: F M
authors.initials: FM
authors.lastname: Fink
authors.forename: R
authors.initials: R
authors.lastname: Möhle
authors.forename: B
authors.initials: B
authors.lastname: Meister
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007223:Infant; D019169:Jurkat Cells; D017254:Leukemic Infiltration / Q000175:diagnosis*; D008099:Liver / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000032:analysis* / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4