Survival of leukemic B cells promoted by engagement of the antigen receptor

Chronic lymphocytic leukemia (CLL) is an incurable leukemia characterized b y the slow but progressive accumulation of cells in a CD5(+) B-cell clone. Like the nonmalignant counterparts, B-1 cells, CLL cells often express surf ace immunoglobulin with the capacity to bind autologous structures. Previou sly there has been no established link between antigen-receptor binding and inhibition of apoptosis in CLL. In this work, using primary CLL cells from untreated patients with this disease, it is demonstrated that engagement o f surface IgM elicits a powerful survival program. The response includes in hibition of caspase activity, activation of NF-kappaB, and expression of mc l-1, bcl-2, and bfl-1 in the tumor cells. Blocking phosphatidylinositol 3-k inase (PI3-K), a critical mediator of signals through the antigen receptor, completely abrogated mcl-1 induction and impaired survival in the stimulat ed cells. These data support the contention that CLL cell survival is promo ted by antigen for which the malignant clone has affinity, and suggest that pharmacologic interference with antigen-receptor-derived signals has poten tial for therapy in patients with CLL. (C) 2001 by The American Society of Hematology.