Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy

Approximately 20% of B-lineage acute lymphoblastic leukemias are not cured by traditional chemotherapy, The possibility was examined that residual leu kemic cells that potentially contribute to relapse are harbored in associat ion with fibroblastic stromal cells in the bone marrow. Modulation of cytar abine (Ara-C) and etoposide (VP-16) efficacy by bone marrow stromal cells i n vitro was investigated. Stromal cell coculture was shown to sustain the p roliferation of B-lineage leukemic cells and to reduce leukemic cell apopto sis when exposed to Ara-C or VP-16. Direct contact with stromal cells was e ssential for the protection of leukemic cells during chemotherapy, whereas soluble factors had negligible effect. Specifically, signaling mediated thr ough interaction with the stromal cell adhesion molecule VCAM-1 was require d to maintain the maximum viability of leukemic cells during Ara-C and VP-1 6 exposure. In contrast, the interaction of leukemic cells with fibronectin did not confer significant resistance to either chemotherapeutic agent. Th ese observations suggest a role for the bone marrow microenvironment in mod ulating the response of B-lineage leukemic cells to Ara-C or VP-16, and the y indicate specific molecular interactions that may be important in determi ning the sensitivity of leukemic cells to treatment. (C) 2000 by The American Society of Hematology.