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‐70high and Zap‐70low B‐CLL samples displayed similar levels of surface death receptor TRAIL‐R2, recombinant TRAIL induced cytotoxicity only in a subset of Zap‐70low B‐CLL samples while Zap‐70high 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‐70low but not in Zap‐70high. On the other hand, recombinant TRAIL up‐regulated the expression of several cytokines (IL‐1β, IL‐1α, IL‐8), which have been involved in promoting B‐CLL cell survival. In particular, TRAIL selectively up‐regulated IL‐1β in Zap‐70low B‐CLL samples, while it markedly and selectively up‐regulated its own mRNA and that of cyclooxigenase‐2 (COX‐2) in Zap‐70high. 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. J. Cell. Physiol. 213: 229–236, 2007. © 2007 Wiley‐Liss, Inc.

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