Abstract
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.
Original language | English |
---|---|
Pages (from-to) | 240-9 |
Number of pages | 10 |
Journal | British Journal of Haematology |
Volume | 166 |
Issue number | 2 |
DOIs | |
Publication status | Published - Jul 2014 |
Keywords
- Antineoplastic Combined Chemotherapy Protocols
- Biomarkers, Tumor
- Chemokine CXCL12
- Child
- Culture Media, Conditioned
- Cytokines
- Granulocyte Colony-Stimulating Factor
- Humans
- Mesenchymal Stromal Cells
- Neoplasm Proteins
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Prognosis
- Receptors, CXCR4
- Recurrence
- Remission Induction
- Tumor Cells, Cultured