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

G. Zauli, M. G. Di Iasio, P. Secchiero, M. Dal Bo, D. Marconi, R. Bomben, G. Del Poeta, V. Gattei

Research output: Contribution to journalArticlepeer-review

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 B-CLL 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 B-CLL 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.

Original languageEnglish
Pages (from-to)510-518
Number of pages9
JournalCurrent Cancer Drug Targets
Volume9
Issue number4
DOIs
Publication statusPublished - Jun 2009

Keywords

  • B-CLL
  • Gene expression profile
  • MDM2
  • Nutlin-3
  • p53 pathway

ASJC Scopus subject areas

  • Cancer Research
  • Drug Discovery
  • Pharmacology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this