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MSC-induced SP phenotype leads to chemoresistance
promoting effects on blasts, preliminary results on four patients suggest that cultivating MSC and blasts in autol- ogous conditions would bring a supplemental advantage on blast survival and chemoresistance (Boutin L et al., 2018, unpublished data). This suggests that an intimate crosstalk has taken place in vivo between MSC and blasts and has been conserved in vitro. Recently, Moschoi et al.31 proposed that mitochondrial transfers from BM stromal cells to AML blasts provided them with a protective effect following chemotherapy. Other communication modes such as exosome exchange, metabolite secretion, and nan- otube formation could also be suggested to participate in this process and must be identified to disrupt the stroma- induced chemoresistance of AML blasts.
Induction of SP/chemoresistance phenotype on AML blasts is of major interest to clinicians as ABC transporters implicated in drug/chemotherapy agent efflux could be targeted.32,33 In that context, we have shown that mitox- antrone efflux and blast survival are reversible in vitro by addition of verapamil. However, results from clinical trials using P-glycoprotein inhibitors in AML patients are dis- couraging.34,35 Our data showing that the functionality of the main ABC transporters implicated in MDR36 is pro- moted by blast-MSC interactions, and that this process is
patient-dependent, suggest that it is time to revisit the role of ABC transporters in therapeutic failure in the context of personalized medicine.37,38
In conclusion, our results show the critical role of stro- ma interactions in blast chemoresistance through SP phe- notype promotion and ABC transporter activation. Therefore, targeting these interactions in combination with the development of new improved inhibitors of ABC transporter function39 could be an attractive therapeutic alternative.
Acknowledgments
We thank the molecular core facility of Cochin Institute for transcriptomic analysis. We are very grateful to the polyclinic of Blois and particularly to Dr Denis Burgot as well as all the ortho- pedic surgery staff for providing human bone marrow samples from hip replacement. We thank Dr Cedric Thépenier for the sta- tistical analysis and sharpened advices. We also thank Pr Christophe Martinaud for blast analysis on blood smears.
Funding
This work was supported by grants from Association “Laurette Fugain” (ALF 2013/08) and Association “Vaincre le Cancer- Nouvelles Recherches Biomédicales”.
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