BCL-X EXPRESSION IN MULTIPLE-MYELOMA - POSSIBLE INDICATOR OF CHEMORESISTANCE

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-started bone marrow cells obtained from some patients. Only the antiapoptotic long form of BCL-X (BCL-X-L), w as detected. Because BCL-X-L expression can protect tumor cells from a poptotic death induced by chemotherapeutic agents, we tested the clini cal relevance of expression in 55 archival bone marrow biopsies. The b iopsies were stained by immunohistochemistry, and BCL-X expression was correlated with the subsequent response to treatment. BCL-X expressio n in malignant plasma cells strongly correlated with decreased respons e 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 case s. In addition, BCL-X expression was more frequent in specimens taken from patients at relapse (77%), when compared to those at initial diag nosis (29%). Further support for the association of drug resistance wi th BCL-X-L expression came from studies of the 8226 dox-4O cell line. This line, which expresses p-glycoprotein and serves as a model of mul tidrug resistance in multiple myeloma cells, demonstrated an up-regula ted expression of BCL-X-L, which was relatively specific, in that BCL- 2 or BAX expression was not altered. In addition, dox-40 cells demonst rated a generalized resistance to apoptosis that was induced by severa l different agents. These results indicate that malignant plasma cells can express BCL-X-L and that such expression may be a marker of chemo resistant disease.