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Bryostatin and CD40‐ligand enhance apoptosis resistance and induce expression of cell survival genes in B‐cell chronic lymphocytic leukaemia

1999; Wiley; Volume: 106; Issue: 4 Linguagem: Inglês

10.1046/j.1365-2141.1999.01642.x

1365-2141

Shinichi Kitada, Juan M. Zapata, Michael Andreeff, John C. Reed,

Acute Lymphoblastic Leukemia research

Modulating signal transduction pathways represents a promising approach for altering the biological behaviour of haemopoietic malignancies. B‐cell chronic lymphocytic leukaemia (B‐CLL) cells were treated in vitro with CD40‐ligand (CD40L) (CD154) or the protein kinase C modulator Bryostatin‐1, exploring the effects on: (a) sensitivity to apoptosis induction by chemotherapeutic drugs (fludarabine, dexamethasone) or anti‐Fas antibody; (b) expression of apoptosis‐regulatory proteins (Bcl‐2, Bcl‐X, Mcl‐1, Bax, Bak, BAG‐1, Flip, XIAP); (c) expression of cell surface co‐stimulatory antigens (CD80 [B7.1]; CD54 [ICAM‐1]; CD70); and (d) expression of immune modulatory receptors (CD27, CD40, CD95 [Fas]). CD40L and Bryostatin decreased both spontaneous and drug‐induced apoptosis in most B‐CLL specimens tested. Apoptosis resistance was associated with CD40L‐ and Bryostatin‐induced elevations in the anti‐apoptotic Bcl‐2 family protein Mcl‐1. CD40L also induced striking increases in the levels of the anti‐apoptotic protein Bcl‐X L in B‐CLLs. CD40L stimulated increases in the surface expression of CD40, CD54, CD69, CD70, CD80 and CD95, whereas Bryostatin induced expression of CD40, CD54, CD69 and CD95 but not the co‐stimulatory molecules CD70 and CD80. Despite elevations in the expression of CD95 (Fas), anti‐Fas antibodies failed to induce apoptosis of CD40L‐ and Bryostatin‐treated B‐CLL cells. This Fas‐resistance was associated with increased expression of the Fas‐antagonist Flip in CD40L‐treated, and with elevations in the caspase inhibitor XIAP in Bryostatin‐treated B‐CLLs. The potential anti‐apoptotic properties of CD40L and Bryostatin should be taken into consideration when employing these agents in clinical trials involving patients with B‐CLL.