TY - JOUR
T1 - Disturbed CXCR4/CXCL12 axis in paediatric precursor B-cell acute lymphoblastic leukaemia
AU - van den Berk, Lieke C J
AU - van der Veer, Arian
AU - Willemse, Marieke E
AU - Theeuwes, Myrte J G A
AU - Luijendijk, Mirjam W
AU - Tong, Wing H
AU - van der Sluis, Inge M
AU - Pieters, Rob
AU - den Boer, Monique L
N1 - © 2014 John Wiley & Sons Ltd.
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Biomarkers, Tumor/metabolism
KW - Chemokine CXCL12/metabolism
KW - Child
KW - Culture Media, Conditioned
KW - Cytokines/metabolism
KW - Granulocyte Colony-Stimulating Factor/metabolism
KW - Humans
KW - Mesenchymal Stem Cells/metabolism
KW - Neoplasm Proteins/metabolism
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Prognosis
KW - Receptors, CXCR4/metabolism
KW - Recurrence
KW - Remission Induction
KW - Tumor Cells, Cultured
U2 - 10.1111/bjh.12883
DO - 10.1111/bjh.12883
M3 - Article
C2 - 24697337
SN - 0007-1048
VL - 166
SP - 240
EP - 249
JO - British journal of haematology
JF - British journal of haematology
IS - 2
ER -