Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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Exposure of B Cell Chronic Lymphocytic Leukemia (B-CLL) Cells to Nutlin-3 Induces a Characteristic Gene Expression Profile, which Correlates with Nutlin-3-Mediated Cytotoxicity (Supplementry Table)

Author(s): G. Zauli, M. G. di Iasio, P. Secchiero, M. Dal Bo, D. Marconi, R. Bomben, G. Del Poeta, V. Gattei.

Abstract:

By analyzing the cDNA obtained from 16 B-cell chronic lymphocytic leukemia (B-CLL) patient samples, we found that Nutlin-3, a small molecule inhibitor of MDM2/p53 interaction, induced a characteristic gene expression profile (GEP) signature in 13 out of 16 B-CLL samples. The lack of Nutlin-3-induced GEP signature in 3 out of 16 B-CLL samples was not due to p53 deletion and/or mutation, as demonstrated by FISH analysis and p53 sequencing. Of note, the 3 BCLL samples in which Nutlin-3 did not elicit the GEP signature were also less susceptible to Nutlin-3-mediated cytotoxicity with respect to the remaining 13 B-CLL samples. However, the partial lack of response in these p53 wild-type B-CLL samples was not due to defects in the ability of Nutlin-3 to promote p53 induction, as confirmed by the rapid accumulation of p53 protein at Western blot analysis in response to Nutlin-3 in all samples examined. Upon exposure to Nutlin-3, the genes up-regulated with the highest score in the majority of B-CLL cells were all known p53-target genes, including genes involved in apoptotic pathways, such as FAS and BAX, as well as MDM2. Taken together, our data indicate that the ability of Nutlin-3 to induce a characteristic GEP signature correlates with its cytotoxic potential in p53 wild-type BCLL cells. However, in some p53 wild-type B-CLL samples, the response to Nutlin-3 cannot be predicted on the basis of FISH analysis or p53 sequencing.

Keywords: B-CLL, Nutlin-3, p53 pathway, gene expression profile, MDM2

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Article Details

VOLUME: 9
ISSUE: 4
Year: 2009
Page: [510 - 518]
Pages: 9
DOI: 10.2174/156800909788486777
Price: $58