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Department of Medicine, Veterans Affairs West Los Angeles Hospital and University of California at Los Angeles Medical School, Los Angeles, California 90073 [Y. T., S. R., F-h. X., R. V., M. R., J. B., A. L.]; Department of Biostatistics, University of California at Los Angeles Medical School, Jonsson Cancer Center, Los Angeles, California 90073 [A. F., J. T.]; Kaiser Permanente Hospital, Woodland Hills, California 91365 [J. W.]; and The Burnham Institute, La Jolla, California 92037 [S. K., J. C. R.]
Because murine myeloma plasma cells and normal human lymph node plasma cells express BCL-X, we evaluated BCL-X expression in malignant human plasma cells. BCL-X expression was detected in several human myeloma cell lines, as well as in CD38-sorted bone marrow cells obtained from some patients. Only the antiapoptotic long form of BCL-X (BCL-X-L), was detected. Because BCL-X-L expression can protect tumor cells from apoptotic death induced by chemotherapeutic agents, we tested the clinical relevance of expression in 55 archival bone marrow biopsies. The biopsies were stained by immunohistochemistry, and BCL-X expression was correlated with the subsequent response to treatment. BCL-X expression in malignant plasma cells strongly correlated with decreased response rates in patient groups treated with either melphalan and prednisone or vincristine, Adriamycin, and dexamethasone. Response rates were 83–87% in non-BCL-X-expressing cases and 20–31% in BCL-X-expressing cases. In addition, BCL-X expression was more frequent in specimens taken from patients at relapse (77%), when compared to those at initial diagnosis (29%). Further support for the association of drug resistance with BCL-X-L expression came from studies of the 8226 dox-40 cell line. This line, which expresses p-glycoprotein and serves as a model of multi-drug resistance in multiple myeloma cells, demonstrated an up-regulated expression of BCL-X-L, which was relatively specific, in that BCL-2 or BAX expression was not altered. In addition, dox-40 cells demonstrated a generalized resistance to apoptosis that was induced by several different agents. These results indicate that malignant plasma cells can express BCL-X-L and that such expression may be a marker of chemoresistant disease.
1 This work was supported by research funds of the Veterans Affairs, NIH Grant CA-60181, and American Cancer Society Grant DHP32E.
2 To whom requests for reprints should be addressed, at Hematology-Oncology, Veterans Affairs West Los Angeles Hospital, W111H, 11301 Wilshire Boulevard, Los Angeles, CA 90073. Phone: (310) 268-3622; Fax: (310) 268-4908.
Received 7/24/97. Accepted 11/13/97.
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