2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces differentiation and apoptosis of tumor cells in vitro and in vivo. Here we assessed the effects of CDDO on CCAAT enhancer-binding protein alpha (CEBPA), a transcription factor critical for granulocytic differentiation. In HL60 acute myeloid leukemia (AML) cells, CDDO (0.01 to 2 muM) induces apoptosis in a dose-dependent manner. Conversely, subapoptotic doses of CDDO promote phagocytic activity and granulocytic-monocytic differentiation of HL60 cells through increased de novo synthesis of p42 CEBPA protein. CEBPA translational up-regulation is required for CDDO-induced granulocytic differentiation and depends on the integrity of the CEBPA upstream open reading frame (uORF). Moreover, CDDO increases the ratio of transcriptionally active p42 and the inactive p30 CEBPA isoform, which, in turn, leads to transcriptional activation of CEBPA-regulated genes (eg, GSCFR) and is associated with dephosphorylation of eIF2alpha and phosphorylation of eIF4E. In concordance with these results, CDDO induces a CEBPA ratio change and differentiation of primary blasts from patients with acute myeloid leukemia (AML). Because AML is characterized by arrested differentiation, our data suggest the inclusion of CDDO in the therapy of AML characterized by dysfunctional CEBPA expression.

Koschmieder, S., D'Alò, F., Radomska, H., Schöneich, C., Chang, J., Konopleva, M., et al. (2007). CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha. BLOOD, 110(10), 3695-3705 [10.1182/blood-2006-11-058941].

CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha

VOSO, MARIA TERESA;
2007-11-15

Abstract

2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces differentiation and apoptosis of tumor cells in vitro and in vivo. Here we assessed the effects of CDDO on CCAAT enhancer-binding protein alpha (CEBPA), a transcription factor critical for granulocytic differentiation. In HL60 acute myeloid leukemia (AML) cells, CDDO (0.01 to 2 muM) induces apoptosis in a dose-dependent manner. Conversely, subapoptotic doses of CDDO promote phagocytic activity and granulocytic-monocytic differentiation of HL60 cells through increased de novo synthesis of p42 CEBPA protein. CEBPA translational up-regulation is required for CDDO-induced granulocytic differentiation and depends on the integrity of the CEBPA upstream open reading frame (uORF). Moreover, CDDO increases the ratio of transcriptionally active p42 and the inactive p30 CEBPA isoform, which, in turn, leads to transcriptional activation of CEBPA-regulated genes (eg, GSCFR) and is associated with dephosphorylation of eIF2alpha and phosphorylation of eIF4E. In concordance with these results, CDDO induces a CEBPA ratio change and differentiation of primary blasts from patients with acute myeloid leukemia (AML). Because AML is characterized by arrested differentiation, our data suggest the inclusion of CDDO in the therapy of AML characterized by dysfunctional CEBPA expression.
15-nov-2007
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/15 - MALATTIE DEL SANGUE
English
CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Cells, Cultured; Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-4E; Gene Expression Regulation, Leukemic; Genes, abl; Granulocytes; HL-60 Cells; Humans; K562 Cells; Leukemia, Myeloid; Myeloid Progenitor Cells; Oleanolic Acid; Phosphorylation; Protein Biosynthesis; Up-Regulation
Koschmieder, S., D'Alò, F., Radomska, H., Schöneich, C., Chang, J., Konopleva, M., et al. (2007). CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha. BLOOD, 110(10), 3695-3705 [10.1182/blood-2006-11-058941].
Koschmieder, S; D'Alò, F; Radomska, H; Schöneich, C; Chang, J; Konopleva, M; Kobayashi, S; Levantini, E; Suh, N; Di Ruscio, A; Voso, Mt; Watt, J; Santhanam, R; Sargin, B; Kantarjian, H; Andreeff, M; Sporn, M; Perrotti, D; Berdel, W; Müller Tidow, C; Serve, H; Tenen, D
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/118073
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