UNBALANCED EXPRESSION OF BCL-2 FAMILY PROTEINS IN FOLLICULAR LYMPHOMA- CONTRIBUTION OF CD40 SIGNALING IN PROMOTING SURVIVAL

Although highly responsive, advanced stage follicular lymphoma (FL) is not curable with conventional treatment. This relative resistance is thought to be due to the t(14;18) that results in the constitutive ove rexpression of the death-inhibiting protein bcl-2. However, the observ ation that FL cells are sensitive to treatment in vivo and prone to ap optosis on in vitro culture questions whether bcl-2 alone is responsib le for the pathogenesis and clinical behavior of this disease, Therefo re, multiple genes are likely to be involved in both the lymphomagenes is and the clinical course of FL. We examined whether expression of ot her bcl-2 family genes might also be operative. Here, we show that FL cells display a different pattern of expression of bcl-2 family protei ns from normal germinal center (GC) B cells that are thought to be the ir normal counterpart. FL cells express the death-suppressor proteins bcl-2, bcl-x(L), and mcl-1; whereas GC B cells express bcl-x(L) and mc l-1 but also the proapoptotic proteins bax-alpha and bad. Although mai ntaining constitutive levels of bcl-2 and mcl-1, FL cells are not prot ected from apoptosis when cultured in vitro. Their propensity to under go apoptosis is temporally associated with downregulation of bcl-x(L). More importantly, activation of FL cells via CD40 not only prevents d ownregulation but increases the level of bcl-x(L) expression and resul ts in promotion of survival. These results support the hypothesis that the overexpression of bcl-2 is not the only antiapoptotic mechanism r esponsible for the pathogenesis of FL, Survival of FL cells is determi ned by a number of death-inhibiting proteins, among which bcl-x(L) app ears to have the most critical role, Moreover, these findings are cons istent with the hypothesis that, although FL cells are malignant, they respond to microenvironmental signals such as CD40L that appear to co ntribute to their survival through the upregulation of death-inhibitin g proteins, (C) 1998 by The American Society of Hematology.