ZAP-70 Modulates Response of CLL Cells to TRAIL

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J Cell Physiol. 2007 May 2; [Epub ahead of print]

Differential gene expression induction by TRAIL in B chronic

lymphocytic leukemia (B-CLL) cells showing high versus low levels of

Zap-70.

Secchiero P, di Iasio MG, Gonelli A, Barbarotto E, Melloni E,

Tiribelli M, Chiaruttini C, Zauli G.

Department of Morphology and Embryology, Human Anatomy Section,

University of Ferrara, Ferrara, Italy.

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. J. Cell.

Physiol. © 2007 Wiley-Liss, Inc.

PMID: 17476690 [PubMed - as supplied by publisher]