Differential gene expression induction by TRAIL in B chronic lymphocytic leukemia (B-CLL) cells showing high versus low levels of Zap-70.
Among 14 peripheral blood samples obtained from patients affected by B chronic lymphocytic leukemia (B-CLL) at initial stages (Rai 0-1) of the disease, 6 showed intermediate/high levels of Zap-70 while 8 displayed low/absent levels of Zap-70. Although Zap-70(high) and Zap-70(low) B-CLL samples displayed similar levels of surface death receptor TRAIL-R2, recombinant TRAIL induced cytotoxicity only in a subset of Zap-70(low) B-CLL samples while Zap-70(high) were completely resistant to TRAIL. The gene expression profiling was next analyzed in all B-CLL samples treated with either chlorambucil or recombinant TRAIL. While chlorambucil up-regulated the steady-state mRNA levels of known p53 target genes, such as PUMA, Fas/CD95 and MDM2 in all B-CLL samples examined, it significantly down-regulated survivin in Zap-70(low) but not in Zap-70(high). On the other hand, recombinant TRAIL up-regulated the expression of several cytokines (IL-1beta, IL-1alpha, IL-8), which have been involved in promoting B-CLL cell survival. In particular, TRAIL selectively up-regulated IL-1beta in Zap-70(low) B-CLL samples, while it markedly and selectively up-regulated its own mRNA and that of cyclooxigenase-2 (COX-2) in Zap-70(high). Taken together, our findings suggest that a significant expression of Zap-70 modulate the response of B-CLL to TRAIL, which might represents an initial step in the pathogenesis of B-CLL.
Secchiero
Paola
P
Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Ferrara, Italy. secchier@mail.umbi.umd.edu
di Iasio
Maria Grazia
MG
Gonelli
Arianna
A
Barbarotto
Elisa
E
Melloni
Elisabetta
E
Tiribelli
Mario
M
Chiaruttini
Cristina
C
Zauli
Giorgio
G
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002699:Chlorambucil / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D002699:Chlorambucil; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human