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Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia

Nature Cell Biology volume 14, pages 276–286 (2012)Cite this article

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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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Figure 1: Bone marrow stromal cells enhanced GSH synthesis in CLL cells and relieved their ROS stress.
Figure 2: Critical role of GSH in mediating stromal protection of CLL cells from spontaneous and drug-induced cell death.
Figure 3: The LMW fraction of the stromal medium enhanced GSH synthesis in CLL cells and promoted cell survival.
Figure 4: Generation of cysteine by bone marrow stromal cells was essential to enhance GSH synthesis in CLL cells and promote their survival.
Figure 5: Leukaemia cells (CLL) exhibited a low ability to directly use cystine and were dependent on stromal cells to convert cystine to cysteine for GSH synthesis.
Figure 6: Overcoming stromal-induced drug resistance in CLL cells by depleting GSH in leukaemia cells or blocking cystine uptake by stromal cells.
Figure 7: Effect of abolishing GSH protection on CLL cells by blocking cystine uptake by stromal cells 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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Authors and Affiliations

  1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

    Wan Zhang, Dunyaporn Trachootham, Jinyun Liu, Gang Chen, Helene Pelicano, Celia Garcia-Prieto, Weiqin Lu & Peng Huang

  2. The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, Jiangxi 330006, China

    Wan Zhang

  3. Faculty of Dentistry, Thammasat University, Pathum-thani 12121, Thailand

    Dunyaporn Trachootham

  4. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA

    Jinyun Liu & Peng Huang

  5. Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

    Jan A. Burger & Michael J. Keating

  6. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, Ohio 43210, USA

    Carlo M. Croce

  7. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

    William Plunkett

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Contributions

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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Correspondence to Peng Huang.

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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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