Inducible activation of CEBPB, a gene negatively regulated by BCR/ABL, inhibits proliferation and promotes differentiation of BCR/ABL-expressing cells

Clara Guerzoni, Michela Bardini, Samanta A. Mariani, Giovanna Ferrari-Amorotti, Paolo Neviani, Maria Luisa Panno, Ying Zhang, Robert Martinez, Danilo Perrotti, Bruno Calabretta

Research output: Contribution to journalArticlepeer-review

Abstract

Translational regulation by oncogenic proteins may be a rapid and efficient mechanism to modulate gene expression. We report here the identification of the CEBPB gene as a target of translational regulation in myeloid precursor cells transformed by the BCR/ABL oncogene. Expression of CEBPB was repressed in 32D-BCR/ABL cells and reinduced by imatinib (STI571) via a mechanism that appears to depend on expression of the CUG-repeat RNA-binding protein CUGBP1 and the integrity of the CUG-rich intercistronic region of c/ebpβ mRNA. Constitutive expression or conditional activation of wildtype CEBPB induced differentiation and inhibited proliferation of 32D-BCR/ABL cells in vitro and in mice, but a DNA binding-deficient CEBPB mutant had no effect. The proliferation-inhibitory effect of CEBPB was, in part, mediated by the CEBPB-induced GADD45A gene. Because expression of CEBPB (and CEBPA) is low in the blast crisis (BC) stage of chronic myelogenous leukemia (CML) and is inversely correlated with BCR/ABL tyrosine kinase levels, these findings point to the therapeutic potential of restoring C/EBP activity in CML-BC and, perhaps, other types of acute leukemia.

Original languageEnglish
Pages (from-to)4080-4089
Number of pages10
JournalBlood
Volume107
Issue number10
DOIs
Publication statusPublished - May 15 2006

ASJC Scopus subject areas

  • Hematology

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