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
Department of Paediatric Oncology/Haematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
Br J Haematol. 2014 Jul;166(2):240-9. doi: 10.1111/bjh.12883. Epub 2014 Apr 4.
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.
浸润骨髓（BM）的恶性细胞会干扰支持细胞的正常细胞行为，从而形成恶性微环境。我们发现，与正常单核造血细胞相比，小儿前体B细胞急性淋巴细胞白血病（BCP-ALL）细胞中CXCR4受体的表达增加（P < 0·0001）。此外，CXCR4高表达与BCP-ALL的不良预后相关（5年累积复发率±标准误：CXCR4高表达病例为38·4% ± 6·9%，CXCR4低表达病例为12% ± 4·6%，P < 0·0001）。有趣的是，与非白血病对照相比，诊断性BCP-ALL样本中CXCR4配体（CXCL12）的骨髓水平低2·7倍（P = 0·005）。诱导化疗可使CXCL12水平恢复正常。用普乐沙福阻断CXCR4受体表明，诊断时较低的CXCL12血清水平既不能用白血病细胞的消耗来解释，在这个时间点我们也未观察到骨髓间充质基质细胞（BM-MSC）的CXCL12产生能力发生改变。相反，我们观察到极高密度的白血病细胞在刺激粒细胞集落刺激因子（G-CSF）分泌水平的同时，会对BM-MSC产生的CXCL12产生负面影响。这些结果表明，高增殖性白血病细胞能够下调参与归巢的细胞因子（CXCL12）的分泌，同时上调参与造血动员的细胞因子（G-CSF）的分泌。因此，干扰CXCR4/CXCL12轴可能是动员BCP-ALL细胞的有效方法。
