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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1926-1932
NEOPLASIA
Stromal cells regulate survival of B-lineage leukemic cells
during chemotherapy
Ryan E. Mudry,
James E. Fortney,
Teresa York,
Brett M. Hall, and
Laura F. Gibson
From the Departments of Pediatrics, Microbiology and
Immunology, and Biology, and the Blood and Marrow Transplantation
Program, Mary Babb Randolph Cancer Center, West Virginia University,
Morgantown, WV.
Approximately 20% of B-lineage acute lymphoblastic leukemias are
not cured by traditional chemotherapy. The possibility was examined
that residual leukemic cells that potentially contribute to relapse are
harbored in association with fibroblastic stromal cells in the bone
marrow. Modulation of cytarabine (Ara-C) and etoposide (VP-16) efficacy
by bone marrow stromal cells in vitro was investigated. Stromal cell
coculture was shown to sustain the proliferation of B-lineage leukemic
cells and to reduce leukemic cell apoptosis when exposed to Ara-C or
VP-16. Direct contact with stromal cells was essential for the
protection of leukemic cells during chemotherapy, whereas soluble
factors had negligible effect. Specifically, signaling mediated through
interaction with the stromal cell adhesion molecule VCAM-1 was required
to maintain the maximum viability of leukemic cells during Ara-C and
VP-16 exposure. In contrast, the interaction of leukemic cells with fibronectin did not confer significant resistance to either
chemotherapeutic agent. These observations suggest a role for the bone
marrow microenvironment in modulating the response of B-lineage
leukemic cells to Ara-C or VP-16, and they indicate specific molecular
interactions that may be important in determining the sensitivity of
leukemic cells to treatment.
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