Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Nat Cell Biol. 2012 Feb 19;14(3):276-86. doi: 10.1038/ncb2432.
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.
组织基质细胞与白血病细胞相互作用，并深刻影响白血病细胞的活力和药物敏感性。在这里，我们展示了骨髓基质细胞调节慢性淋巴细胞白血病（CLL）细胞氧化还原状态并促进细胞存活和耐药性的生化机制。由于 Xc 转运体表达水平低，患者的原代 CLL 细胞对胱氨酸转运用于谷胱甘肽（GSH）合成的能力有限。相比之下，骨髓基质细胞有效地摄取胱氨酸并将其转化为半胱氨酸，然后将其释放到微环境中供 CLL 细胞摄取以促进 GSH 合成。GSH 水平的升高增强了白血病细胞的存活并保护它们免受药物诱导的细胞毒性。此外，使这种保护机制失活会显著增加 CLL 细胞在基质环境中对药物治疗的敏感性。这种基质-白血病相互作用对于 CLL 细胞的存活至关重要，并且代表了一种有效的靶向白血病细胞的关键生化途径，以克服体内的耐药性。
