Abstract
Tissue stromal cells interact with leukaemia cells and profoundly affect their viability and drug sensitivity. Here we show a biochemical mechanism by which bone marrow stromal cells modulate the redox status of chronic lymphocytic leukaemia (CLL) cells and promote cellular survival and drug resistance. Primary CLL cells from patients exhibit a limited ability to transport cystine for glutathione (GSH) synthesis owing to a low expression level of Xc-transporter. In contrast, bone marrow stromal cells effectively import cystine and convert it to cysteine, which is then released into the microenvironment for uptake by CLL cells to promote GSH synthesis. The elevated level of GSH enhances leukaemia cell survival and protects them from drug-induced cytotoxicity. Furthermore, disabling this protective mechanism significantly sensitizes CLL cells to drug treatment in the stromal environment. This stromal–leukaemia interaction is critical for CLL cell survival and represents a key biochemical pathway for effectively targeting leukaemia cells to overcome drug resistance in vivo.
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Acknowledgements
The authors thank D. H. Hawke for expert assistance in LC–MS/MS analysis of cystine and cysteine, and B. A. Hayes, A. G. Melendez, M. A. Ogasawara, L. Feng and H. Zhang for technical assistance and helpful discussions. This work was supported in part by grants CA085563 and CA100428 from the National Institutes of Health, grant PR110322 from CPRIT and a grant for the CLL Global Research Foundation.
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W.Z.: project planning, experimental work, data analysis and manuscript writing; D.T., J.L., G.C., C.G.P. and W.L.: experimental work and data analysis; H.P., J.A.B. and W.P.: project planning and data interpretation; C.M.C.: provided Tcl-1 transgenic mice; M.J.K.: provided CLL specimens and participated in project planning and data interpretation; P.H.: project planning, data analysis and manuscript writing.
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Zhang, W., Trachootham, D., Liu, J. et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat Cell Biol 14, 276–286 (2012). https://doi.org/10.1038/ncb2432
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DOI: https://doi.org/10.1038/ncb2432
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