LOSS OF FUNCTIONAL CELL-SURFACE TRANSFORMING-GROWTH-FACTOR-BETA (TGF-BETA) TYPE-1 RECEPTOR CORRELATES WITH INSENSITIVITY TO TGF-BETA IN CHRONIC LYMPHOCYTIC-LEUKEMIA

Chronic lymphocytic leukemia (CLL) is the most common form of adult le ukemia in Western countries, and there is significant variability in s urvival within CLL clinical stages, Earlier studies showed that CLL ce lls produce and are usually growth inhibited by transforming growth fa ctor beta type 1 (TGF-beta 1), suggesting a mechanism for the clinical ly indolent course of most CLL, Here we studied the mechanism by which CLL cells from about one-third of the patients are insensitive to TGF -beta 1. Of the 13 patients studied, CLL cells isolated from the perip heral blood of 8 patients were sensitive to growth inhibition by TGF-b eta 1, as determined by incorporation of tritiated thymidine, whereas those from 5 patients were completely resistant to TGF-beta 1, As judg ed by binding of radiolabeled TGF-beta 1 followed by cross-linking and immunoprecipitation with anti-receptor antisera, CLL cells sensitive to TGF-beta 1 exhibited normal cell surface expression of both types 1 and 2 TGF-beta receptors, In contrast, all CLL cells resistant to TGF -beta 1 exhibited no detectable surface type I receptors able to bind TGF-beta 1, but normal expression of type II receptors, Both TGF-beta 1-sensitive and TGF-beta 1-resistant CLL cells contained normal amount s of both type 1 and type 2 receptor mRNAs. Specific loss of type 1 re ceptor expression represents a new mechanism by which cells acquire re sistance to TGF-beta 1-mediated growth inhibition in the development a nd progression of human lymphoproliferative malignancies.