CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha.
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.
Department of Medicine, Hematology and Oncology, University of Münster, Münster Germany. steffen.koschmieder@ukmuenster.de
Steffen
S
Koschmieder
Francesco
F
D'Alò
Hanna
H
Radomska
Christine
C
Schöneich
Ji Suk
JS
Chang
Marina
M
Konopleva
Susumu
S
Kobayashi
Elena
E
Levantini
Nanjoo
N
Suh
Annalisa
A
Di Ruscio
Maria Teresa
MT
Voso
Julie C
JC
Watt
Ramasamy
R
Santhanam
Bülent
B
Sargin
Hagop
H
Kantarjian
Michael
M
Andreeff
Michael B
MB
Sporn
Danilo
D
Perrotti
Wolfgang E
WE
Berdel
Carsten
C
Müller-Tidow
Hubert
H
Serve
Daniel G
DG
Tenen
D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016313:Genes, abl; D006098:Granulocytes / Q000166:cytology* / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology*; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D022763:CCAAT-Enhancer-Binding Protein-alpha; D015852:Eukaryotic Initiation Factor-2; D039561:Eukaryotic Initiation Factor-4E; D009828:Oleanolic Acid