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.
Disturbed CXCR4/CXCL12 axis in paediatric precursor B‐cell acute lymphoblastic leukaemia
Beteiligte:
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.
Beschreibung:
<jats:title>Summary</jats:title><jats:p>Malignant cells infiltrating the bone marrow (<jats:styled-content style="fixed-case">BM</jats:styled-content>) interfere with normal cellular behaviour of supporting cells, thereby creating a malignant niche. We found that <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4‐receptor expression was increased in paediatric precursor B‐cell acute lymphoblastic leukaemia (<jats:styled-content style="fixed-case">BCP</jats:styled-content>‐<jats:styled-content style="fixed-case">ALL</jats:styled-content>) cells compared with normal mononuclear haematopoietic cells (<jats:italic>P </jats:italic><<jats:italic> </jats:italic>0·0001). Furthermore, high <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4‐expression correlated with an unfavourable outcome in <jats:styled-content style="fixed-case">BCP</jats:styled-content>‐<jats:styled-content style="fixed-case">ALL</jats:styled-content> (5‐year cumulative incidence of relapse ± standard error: 38·4% ± 6·9% in <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4‐high <jats:italic>versus</jats:italic> 12% ± 4·6% in <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4‐low expressing cases, <jats:italic>P </jats:italic><<jats:italic> </jats:italic>0·0001). Interestingly, <jats:styled-content style="fixed-case">BM</jats:styled-content> levels of the <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4‐ligand (<jats:styled-content style="fixed-case">CXCL</jats:styled-content>12) were 2·7‐fold lower (<jats:italic>P </jats:italic>=<jats:italic> </jats:italic>0·005) in diagnostic <jats:styled-content style="fixed-case">BCP</jats:styled-content>‐<jats:styled-content style="fixed-case">ALL</jats:styled-content> samples compared with non‐leukaemic controls. Induction chemotherapy restored <jats:styled-content style="fixed-case">CXCL</jats:styled-content>12 levels to normal. Blocking the <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4‐receptor with Plerixafor showed that the lower <jats:styled-content style="fixed-case">CXCL</jats:styled-content>12 serum levels at diagnosis could not be explained by consumption by the leukaemic cells, nor did we observe an altered <jats:styled-content style="fixed-case">CXCL</jats:styled-content>12‐production capacity of <jats:styled-content style="fixed-case">BM</jats:styled-content>‐mesenchymal stromal cells (<jats:styled-content style="fixed-case">BM</jats:styled-content>‐<jats:styled-content style="fixed-case">MSC</jats:styled-content>) at this time‐point. We rather observed that a very high density of leukaemic cells negatively affected <jats:styled-content style="fixed-case">CXCL</jats:styled-content>12‐production by the <jats:styled-content style="fixed-case">BM</jats:styled-content>‐<jats:styled-content style="fixed-case">MSC</jats:styled-content> while stimulating the secretion levels of granulocyte colony‐stimulating factor (G‐<jats:styled-content style="fixed-case">CSF</jats:styled-content>). These results suggest that highly proliferative leukaemic cells are able to down‐regulate secretion of cytokines involved in homing (<jats:styled-content style="fixed-case">CXCL</jats:styled-content>12), while simultaneously up‐regulating those involved in haematopoietic mobilization (G‐<jats:styled-content style="fixed-case">CSF</jats:styled-content>). Therefore, interference with the <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4/<jats:styled-content style="fixed-case">CXCL</jats:styled-content>12 axis may be an effective way to mobilize <jats:styled-content style="fixed-case">BCP</jats:styled-content>‐<jats:styled-content style="fixed-case">ALL</jats:styled-content> cells.</jats:p>