AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia.
The transcription factor CCAAT/enhancer binding protein alpha, or C/EBPalpha, encoded by the CEBPA gene, is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and Cebpa knockout mice exhibit an early block in maturation. Dominant-negative mutations of CEBPA have been found in some patients with acute myeloid leukemia (AML), but not in AML with the t(8;21) translocation which gives rise to the fusion gene RUNX1-CBF2T1 (also known as AML1-ETO) encoding the AML1-ETO fusion protein. RUNX1-CBF2T1 positive-AML blasts had eight-fold lower CEBPA RNA levels and undetectable C/EBPalpha protein levels compared with other subgroups of AML patients. Conditional expression of RUNX1-CBF2T1 in U937 cells downregulated CEBPA mRNA, protein and DNA binding activity. AML1-ETO appears to suppress C/EBPalpha expression indirectly by inhibiting positive autoregulation of the CEBPA promoter. Conditional expression of C/EBPalpha in AML1-ETO-positive Kasumi-1 cells results in neutrophilic differentiation. We suggest that restoring C/EBPalpha expression will have therapeutic implications in RUNX1-CBF2T1-positive leukemias.
Hematology/Oncology Division, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
T
T
Pabst
B U
BU
Mueller
N
N
Harakawa
C
C
Schoch
T
T
Haferlach
G
G
Behre
W
W
Hiddemann
D E
DE
Zhang
D G
DG
Tenen
D000818:Animals; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014178:Translocation, Genetic
C107844:AML1-ETO fusion protein, human; D022763:CCAAT-Enhancer-Binding Protein-alpha; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse; D014157:Transcription Factors