TY - JOUR
T1 - CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer-binding protein alpha
AU - Koschmieder, Steffen
AU - D'Alò, Francesco
AU - Radomska, Hanna
AU - Schöneich, Christine
AU - Ji, Suk Chang
AU - Konopleva, Marina
AU - Kobayashi, Susumu
AU - Levantini, Elena
AU - Suh, Nanjoo
AU - Di Ruscio, Annalisa
AU - Voso, Maria Teresa
AU - Watt, Julie C.
AU - Santhanam, Ramasamy
AU - Sargin, Bülent
AU - Kantarjian, Hagop
AU - Andreeff, Michael
AU - Sporn, Michael B.
AU - Perrotti, Danilo
AU - Berdel, Wolfgang E.
AU - Müller-Tidow, Carsten
AU - Serve, Hubert
AU - Tenen, Daniel G.
PY - 2007/11/15
Y1 - 2007/11/15
N2 - 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 μM) 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 eIF2α 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.
AB - 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 μM) 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 eIF2α 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.
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U2 - 10.1182/blood-2006-11-058941
DO - 10.1182/blood-2006-11-058941
M3 - Article
C2 - 17671235
AN - SCOPUS:36348953256
SN - 0006-4971
VL - 110
SP - 3695
EP - 3705
JO - Blood
JF - Blood
IS - 10
ER -