Advanced Stage Follicular Lymphoma Research Articles

Unbalanced Expression of Bcl-2 Family Proteins in Follicular Lymphoma: Contribution of CD40 Signaling in Promoting Survival

AbstractAlthough 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 overexpression of the death-inhibiting protein bcl-2. However, the observation that FL cells are sensitive to treatment in vivo and prone to apoptosis on in vitro culture questions whether bcl-2 alone is responsible for the pathogenesis and clinical behavior of this disease. Therefore, multiple genes are likely to be involved in both the lymphomagenesis and the clinical course of FL. We examined whether expression of other bcl-2 family genes might also be operative. Here, we show that FL cells display a different pattern of expression of bcl-2 family proteins from normal germinal center (GC) B cells that are thought to be their normal counterpart. FL cells express the death-suppressor proteins bcl-2, bcl-xL, and mcl-1; whereas GC B cells express bcl-xL and mcl-1 but also the proapoptotic proteins bax-α and bad. Although maintaining constitutive levels of bcl-2 and mcl-1, FL cells are not protected from apoptosis when cultured in vitro. Their propensity to undergo apoptosis is temporally associated with downregulation of bcl-xL. More importantly, activation of FL cells via CD40 not only prevents downregulation but increases the level of bcl-xL expression and results in promotion of survival. These results support the hypothesis that the overexpression of bcl-2 is not the only antiapoptotic mechanism responsible for the pathogenesis of FL. Survival of FL cells is determined by a number of death-inhibiting proteins, among which bcl-xL appears to have the most critical role. Moreover, these findings are consistent with the hypothesis that, although FL cells are malignant, they respond to microenvironmental signals such as CD40L that appear to contribute to their survival through the upregulation of death-inhibiting proteins.

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 overexpression of the death-inhibiting protein bcl-2. However, the observation that FL cells are sensitive to treatment in vivo and prone to apoptosis on in vitro culture questions whether bcl-2 alone is responsible for the pathogenesis and clinical behavior of this disease. Therefore, multiple genes are likely to be involved in both the lymphomagenesis and the clinical course of FL. We examined whether expression of other bcl-2 family genes might also be operative. Here, we show that FL cells display a different pattern of expression of bcl-2 family proteins from normal germinal center (GC) B cells that are thought to be their normal counterpart. FL cells express the death-suppressor proteins bcl-2, bcl-xL, and mcl-1; whereas GC B cells express bcl-xL and mcl-1 but also the proapoptotic proteins bax-α and bad. Although maintaining constitutive levels of bcl-2 and mcl-1, FL cells are not protected from apoptosis when cultured in vitro. Their propensity to undergo apoptosis is temporally associated with downregulation of bcl-xL. More importantly, activation of FL cells via CD40 not only prevents downregulation but increases the level of bcl-xL expression and results in promotion of survival. These results support the hypothesis that the overexpression of bcl-2 is not the only antiapoptotic mechanism responsible for the pathogenesis of FL. Survival of FL cells is determined by a number of death-inhibiting proteins, among which bcl-xL appears to have the most critical role. Moreover, these findings are consistent with the hypothesis that, although FL cells are malignant, they respond to microenvironmental signals such as CD40L that appear to contribute to their survival through the upregulation of death-inhibiting proteins.

Is there any place for a wait-and-see policy in stage I0 follicular lymphoma?: A study of 43 consecutive patients in a single center

A wait-and-see policy (WS) does not appear to modify the long-term prognosis of advanced-stage follicular lymphomas (FL), while irradiation of limited stages sometimes causes complications and does not avert distant relapses. Consequently, we decided to test WS in a selected subset of the localized FL, i.e., patients in complete remission (CR) after the initial lymph node biopsy (stage I0). Forty-three previously untreated patients were diagnosed with stage I0 FL and 26 of them were included in the WS. Their median age was 60.3 years; 19 were male and 24 female. All histological slides were reviewed and confirmed the diagnosis of FL. Median follow-up was 6.3 years (y). Thirteen of the 26 untreated patients are still relapse-free, while six relapsed locally only (median: 4.2 years after diagnosis), and reattained CR with radiotherapy. Seven patients relapsed at distant sites (median: 1 year after diagnosis). No localized relapses were observed in the treated group, but there were 7 distant relapses. The use of WS in stage I0 FL did not appear to modify the prognosis of these patients. Furthermore, we observed two distinct patterns of relapse (local and distant) that are difficult to differentiate at onset.