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Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis

¹ Stem Cell Biology Section, Department of Haematology and Kennedy Institute of Rheumatology, Imperial College
² Cancer Research–UK Labs and the Department of Cancer Medicine
³ Cancer Research-UK, London Research Institute, HSC Laboratory; London, UK

Correspondence: Francesco Dazzi, Department of Haematology, Hammersmith Campus, Imperial College, Du Cane Road, London W12 0NN, UK. E-mail: f.dazzi{at}imperial.ac.uk

ABSTRACT

Background: Residual disease of chronic myeloid leukaemia (CML) following imatinib treatment has been attributed to the presence of a quiescent leukaemic stem cell intrinsically resistant to imatinib. Mesenchymal stromal cells (MSC) in the bone marrow may favour leukemia persistence and progression by preserving proliferation and self-renewal of malignant progenitors.

Design and methods: BV173 or primary CML cells were cocultured with human MSC and imatinib cell death was then measured. The role of pro-and anti-apoptotic proteins as well as of the chemokine CXCL12 have been evaluated in this context. We also studied the ability of BV173 cells to repopulate NOD/SCID mice following in-vitro exposure to imatinib and MCS.

Results: Whilst imatinib induced dose-dependent apoptosis of BV173 cells and CML primary cells, the co-culture with MSC protected both CML cell types. Molecular analysis indicated that MSC reduced caspase-3 activation and modulated the expression of the anti-apoptotic protein Bcl-XL. Furthermore, the exposure of CML cells to imatinib in the presence of MSC preserved the ability of the leukemia to engraft into NOD/SCID mice. We observed that CML cells and MSC express functional levels of CXCR4 and CXCL12, respectively. Finally, the CXCR4 antagonist, AMD3100 restored apoptosis by imatinib and the susceptibility of the SCID leukemia repopulating cells to the TK inhibitor.

Conclusions: Human MSC mediate protection of CML cells from imatinib-induced apoptosis. Disruption of CXCL12/CXCR4 axis at least in part restores sensitivity to imatinib. The combination of anti-CXCR4 antagonists with TK inhibitors may represent a powerful approach in the treatment of CML.

Key words: chronic myeloid leukemia, mesenchymal stem cells, chemokines, imatinib.