Disturbed CXCR4/CXCL12 axis in paediatric precursor B-cell acute lymphoblastic leukaemia

Lieke C J van den Berk, Arian van der Veer, Marieke E Willemse, Myrte J G A Theeuwes, Mirjam W Luijendijk, Wing H Tong, Inge M van der Sluis, Rob Pieters, Monique L den Boer

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)240-9
Number of pages10
JournalBritish Journal of Haematology
Volume166
Issue number2
DOIs
Publication statusPublished - 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

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