| Autor: |
Smeets MWE; Dept. of Pediatrics, Erasmus MC-Sophia, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht., Steeghs EMP; Dept. of Pediatrics, Erasmus MC-Sophia, Rotterdam., Orsel J; Princess Máxima Center for Pediatric Oncology, Utrecht., Stalpers F; Princess Máxima Center for Pediatric Oncology, Utrecht., Vermeeren MMP; Princess Máxima Center for Pediatric Oncology, Utrecht., Veltman CHJ; Princess Máxima Center for Pediatric Oncology, Utrecht., Slenders L; Princess Máxima Center for Pediatric Oncology, Utrecht., Nierkens S; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Center for Translational Immunology, University Medical Center, Utrecht., Van de Ven C; Princess Máxima Center for Pediatric Oncology, Utrecht., Den Boer ML; Dept. of Pediatrics, Erasmus MC-Sophia, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht. m.l.denboer@prinsesmaximacentrum.nl. |
| Abstrakt: |
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can hijack the normal bone marrow microenvironment to create a leukemic niche which facilitates blast cell survival and promotes drug resistance. Bone marrow-derived mesenchymal stromal cells (MSC) mimic this protective environment in ex vivo co-cultures with leukemic cells obtained from children with newly diagnosed BCP-ALL. We examined the potential mechanisms of this protection by RNA sequencing of flow-sorted MSC after co-culture with BCP-ALL cells. Leukemic cells induced an interferon (IFN)-related gene signature in MSC, which was partially dependent on direct cell-cell signaling. The signature was selectively induced by BCP-ALL cells, most profoundly by ETV6-RUNX1-positive ALL cells, as co-culture of MSC with healthy immune cells did not provoke a similar IFN signature. Leukemic cells and MSC both secreted IFNα and IFNβ, but not IFNγ. In line, the IFN gene signature was sensitive to blockade of IFNα/β signaling, but less to that of IFNγ. The viability of leukemic cells and level of resistance to three chemotherapeutic agents was not affected by interference with IFN signaling using selective IFNα/β inhibitors or silencing of IFN-related genes. Taken together, our data suggest that the leukemia-induced expression of IFNα/β-related genes by MSC does not support survival of BCP-ALL cells but may serve a different role in the pathobiology of BCP-ALL. |
