Disturbed CXCR4/CXCL12 axis in paediatric precursor B-cell acute lymphoblastic leukaemia.
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.
Department of Paediatric Oncology/Haematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
Lieke C J
LC
van den Berk
Arian
A
van der Veer
Marieke E
ME
Willemse
Myrte J G A
MJ
Theeuwes
Mirjam W
MW
Luijendijk
Wing H
WH
Tong
Inge M
IM
van der Sluis
Rob
R
Pieters
Monique L
ML
den Boer
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D002648:Child; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012008:Recurrence; D012074:Remission Induction; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; D016207:Cytokines; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor
BM-MSC; CXCL12; CXCR4; Plerixafor; paediatric acute lymphoblastic leukaemia