High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia

Abstract

Summary. 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.

Transfection of antisense core 2 β1,6-N-acetylglucosaminyltransferase-1 cDNA suppresses selectin ligand expression and tissue infiltration of B-cell precursor leukemia cells

“…19,[26][27][28] BCP-leukemia cells also expressed CXCR4 and infiltrated into peripheral organs through SDF-1-induced activation. 26,29,30 On the other hand, Naiyer et al 31 reported that SDF-1 expression and SDF-1-induced transendothelial migration were initiated by tethering of CB-CD34 þ cells through interaction with E-selectin on endothelial cells. The present study revealed selectin-dependent cell adhesion capability and CXCR4 expression in KM3 cells (see Supplementary Figure S2).…”

No role for CXCL12–G801A polymorphism in the development of extramedullary disease in acute myeloid leukemia

“…A significant correlation between high-membrane level of CXCR4 and the enlargement of spleen or liver was found, independently of the count of lymphoblasts in the circulation. 5 Finally, elevated level of submicron plasma membrane vesicles expressing CXCR4 has been detected in the blood and BM fluids of AML patients, providing further evidence that the CXCR4-CXCL12 axis intervenes in AML cell trafficking and tissue dissemination. 6 Letters to the Editor A genetic determinant potentially affecting HPC mobilization is represented by a single-nucleotide polymorphism (SNP) in CXCL12 (G801A), which has been associated with higher number of CD34 þ cells mobilized in the PB when the less common A allele was present; 7 in this study on 63 patients with malignancies who underwent HPC mobilization with hematopoietic growth factors, the A allele was present in 67% of good mobilizers as compared to 36% of the intermediate/poor mobilizers.…”

Overexpression of CXCR4 predicts adverse overall and event‐free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype

“…[2][3][4][5][6] Patients with acute myeloid leukemia (AML), although initially often responsive to current therapy, generally have a poor prognosis. As a result, new molecular targets for therapy and biological markers of prognosis are needed.…”