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

Tissue stromal cells interact with leukemia 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 leukemia (CLL) cells and promote cellular survival and drug resistance. Primary CLL cells from patients exhibit limited ability to transport cystine for glutathione (GSH) synthesis due to a low expression of Xc- transporter, while 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 GSH enhances leukemia cell survival and protects them from drug-induced cytotoxicity. Furthermore, disabling this protective mechanism significantly sensitizes CLL cells to drug treatment in stromal environment. This stromal-leukemia interaction is critical for CLL cell survival and represents a key biochemical pathway for effectively targeting leukemia cells to overcome drug resistance in vivo.