Disturbed CXCR4/CXCL12 axis in paediatric precursor B‐cell acute lymphoblastic leukaemia. (4th April 2014)

• Record Type: Journal Article
• Authors: van den Berk, Lieke C. J.; van der Veer, Arian; Willemse, Marieke E.; Theeuwes, Myrte J. G. A.; Luijendijk, Mirjam W.; Tong, Wing H.; van der Sluis, Inge M.; Pieters, Rob; den Boer, Monique L.
• Is Part Of: British journal of haematology. Volume 166:Number 2(2014:Jul.)
• Page Start: 240
• Page End: 249
• Publication Date: 2014-04-04
• Subjects: paediatric acute lymphoblastic leukaemia -- CXCR4 -- CXCL12 -- BM‐MSC -- Plerixafor; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.12883
• Languages: English
• ISSNs: 0007-1048

Abstract

Summary: Malignant cells infiltrating the bone marrow (BM) interfere with normal cellular behaviour of supporting cells, thereby creating a malignant niche. We found that CXCR4‐receptor expression was increased in paediatric precursor B‐cell acute lymphoblastic leukaemia (BCP‐ALL) cells compared with normal mononuclear haematopoietic cells ( P < 0·0001). Furthermore, high CXCR4‐expression correlated with an unfavourable outcome in BCP‐ALL (5‐year cumulative incidence of relapse ± standard error: 38·4% ± 6·9% in CXCR4‐high versus 12% ± 4·6% in CXCR4‐low expressing cases, P < 0·0001). Interestingly, BM levels of the CXCR4‐ligand (CXCL12) were 2·7‐fold lower ( P = 0·005) in diagnostic BCP‐ALL samples compared with non‐leukaemic controls. Induction chemotherapy restored CXCL12 levels to normal. Blocking the CXCR4‐receptor with Plerixafor showed that the lower CXCL12 serum levels at diagnosis could not be explained by consumption by the leukaemic cells, nor did we observe an altered CXCL12‐production capacity of BM‐mesenchymal stromal cells (BM‐MSC) at this time‐point. We rather observed that a very high density of leukaemic cells negatively affected CXCL12‐production by the BM‐MSC while stimulating the secretion levels of granulocyte colony‐stimulating factor (G‐CSF). These results suggest that highly proliferative leukaemic cells are able to down‐regulate secretion of cytokines involved in homing (CXCL12), while simultaneously up‐regulating those involved in haematopoietic mobilization (G‐CSF). Therefore, interference with the CXCR4/CXCL12 axis may be an effective way to mobilize BCP‐ALL cells.