Disturbed CXCR 4/ CXCL 12 axis in paediatric precursor B‐cell acute lymphoblastic leukaemia

• Published in: British journal of haematology 2014-07, Vol.166 (2), p.240-249
• Main 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.
• Format: Article
• Language: English
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.12883

Malignant cells infiltrating the bone marrow ( BM ) interfere with normal cellular behaviour of supporting cells, thereby creating a malignant niche. We found that CXCR 4‐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 CXCR 4‐expression correlated with an unfavourable outcome in BCP ‐ ALL (5‐year cumulative incidence of relapse ± standard error: 38·4% ± 6·9% in CXCR 4‐high versus 12% ± 4·6% in CXCR 4‐low expressing cases, P  <   0·0001). Interestingly, BM levels of the CXCR 4‐ligand ( CXCL 12) were 2·7‐fold lower ( P  =   0·005) in diagnostic BCP ‐ ALL samples compared with non‐leukaemic controls. Induction chemotherapy restored CXCL 12 levels to normal. Blocking the CXCR 4‐receptor with Plerixafor showed that the lower CXCL 12 serum levels at diagnosis could not be explained by consumption by the leukaemic cells, nor did we observe an altered CXCL 12‐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 CXCL 12‐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 ( CXCL 12), while simultaneously up‐regulating those involved in haematopoietic mobilization (G‐ CSF ). Therefore, interference with the CXCR 4/ CXCL 12 axis may be an effective way to mobilize BCP ‐ ALL cells.