Unbalanced expression of bcl-2 family proteins in follicular lymphoma: Contribution of CD40 signaling in promoting survival

被引:109
作者
Ghia, P
Boussiotis, VA
Schultze, JL
Cardoso, AA
Dorfman, DM
Gribben, JG
Freedman, AS
Nadler, LM
机构
[1] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[3] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Boston, MA USA
关键词
D O I
10.1182/blood.V91.1.244.244_244_251
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-x(L), and mcl-1; whereas GC B cells express bcl-x(L) and mcl-1 but also the proapoptotic proteins bax-alpha 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-x(L). More importantly, activation of FL cells via CD40 not only prevents downregulation but increases the level of bcl-x(L) 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-x(L) 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, (C) 1998 by The American Society of Hematology.
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页码:244 / 251
页数:8
相关论文
共 62 条
[1]   GENERATION OF MEMORY B-CELLS AND PLASMA-CELLS IN-VITRO [J].
ARPIN, C ;
DECHANET, J ;
VANKOOTEN, C ;
MERVILLE, P ;
GROUARD, G ;
BRIERE, F ;
BANCHEREAU, J ;
LIU, YJ .
SCIENCE, 1995, 268 (5211) :720-722
[2]   Overexpression of the death-promoting gene bax-alpha which is downregulated in breast cancer restores sensitivity to different apoptotic stimuli and reduces tumor growth in SCID mice [J].
Bargou, RC ;
Wagener, C ;
Bommert, K ;
Mapara, MY ;
Daniel, PT ;
Arnold, W ;
Dietel, M ;
Guski, H ;
Feller, A ;
Royer, HD ;
Dorken, B .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 97 (11) :2651-2659
[3]   BCL-X, A BCL-2-RELATED GENE THAT FUNCTIONS AS A DOMINANT REGULATOR OF APOPTOTIC CELL-DEATH [J].
BOISE, LH ;
GONZALEZGARCIA, M ;
POSTEMA, CE ;
DING, LY ;
LINDSTEN, T ;
TURKA, LA ;
MAO, XH ;
NUNEZ, G ;
THOMPSON, CB .
CELL, 1993, 74 (04) :597-608
[4]  
BOYD JM, 1995, ONCOGENE, V11, P1921
[5]  
BROOME HE, 1995, J IMMUNOL, V155, P2311
[6]  
CARBONE A, 1995, AM J PATHOL, V147, P912
[7]   Bax-independent inhibition of apoptosis by Bcl-x(L) [J].
Cheng, EHY ;
Levine, B ;
Boise, LH ;
Thompson, CB ;
Hardwick, JM .
NATURE, 1996, 379 (6565) :554-556
[8]   INDUCTION OF APOPTOSIS BY THE BCL-2 HOMOLOG BAK [J].
CHITTENDEN, T ;
HARRINGTON, EA ;
OCONNOR, R ;
FLEMINGTON, C ;
LUTZ, RJ ;
EVAN, GI ;
GUILD, BC .
NATURE, 1995, 374 (6524) :733-736
[9]   THE ROLE OF BCL-X(L) IN CD40-MEDIATED RESCUE FROM ANTI-MU-INDUCED APOPTOSIS IN WEHI-231 B-LYMPHOMA-CELLS [J].
CHOI, MSK ;
BOISE, LH ;
GOTTSCHALK, AR ;
QUINTANS, J ;
THOMPSON, CB ;
KLAUS, GGB .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1995, 25 (05) :1352-1357
[10]   CLONING AND STRUCTURAL-ANALYSIS OF CDNAS FOR BCL-2 AND A HYBRID BCL-2/IMMUNOGLOBULIN TRANSCRIPT RESULTING FROM THE T(14-18) TRANSLOCATION [J].
CLEARY, ML ;
SMITH, SD ;
SKLAR, J .
CELL, 1986, 47 (01) :19-28