The oncogene DEK promotes leukemic cell survival and is downregulated by both nutlin-3 and chlorambucil in B-chronic lymphocytic leukemic cells

Paola Secchiero, Rebecca Voltan, Maria Grazia Di Iasio, Elisabetta Melloni, Mario Tiribelli, Giorgio Zauli

Research output: Contribution to journalArticle

Abstract

Purpose: To characterize the role of the oncogene DEK in modulating the response to either Nutlin-3, a small-molecule inhibitor of the MDM2/p53 interaction, or chlorambucil in primary B-chronic lymphocytic leukemia (B-CLL) cells. Experimental Design: DEK mRNA and protein levels were evaluated in primary B-CLL samples (n = 21), p53wild-type SKW6.4, p53 mutated BJAB lymphoblastoid cell lines, and normal CD19+ B lymphocytes-treated Nutlin-3 or chlorambucil (10 μmol/L, each). Knocking down experiments with either p53 or DEK small interfering RNA (siRNA) were done to investigate the potential role of p53 in controlling the expression of DEK and the role of DEK in leukemic cell survival/apoptosis. Results: Both Nutlin-3 and chlorambucil downregulated DEK in primary B-CLL samples (n = 21) and SKW6.4 but not in BJAB cells. Knocking down p53 attenuated the effect of Nutlin-3 on DEK expression, whereas knocking down DEK significantly increased both spontaneous and Nutlin-3-induced apoptosis. Conversely, counteracting DEK downmodulation by using p53 small interfering RNA reduced Nutlin-3-mediated apoptosis. On the other hand, Nutlin-3 potently induced p53 accumulation, but it did not affect DEK levels in normal CD19+ B lymphocytes. Conclusions: These data show that the downregulation of DEK in response to either Nutlin-3 or chlorambucil represents an important molecular determinant in the cytotoxic response of leukemic cells, and suggest that strategies aimed to downregulate DEK might improve the therapeutic potential of these drugs.

Original languageEnglish
Pages (from-to)1824-1833
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number6
DOIs
Publication statusPublished - Mar 15 2010

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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