The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B.

Frank R, Zhang J, Uchida H, Meyers S, Hiebert SW, Nimer SD
Oncogene. 1995 11 (12): 2667-74

PMID: 8545124

The t(8;21) translocation, commonly found in acute myelogenous leukemia (AML), generates a fusion protein containing N-terminal AML1 and C-terminal ETO amino acids. The human AML1 gene encodes several related proteins that specifically bind to the sequence TGT/cGGT, located in the promoter regions of a variety of hematopoietic growth factor genes. To examine the abilities of the AML1B protein (which contains 479 amino acids), a shorter AML1A isoform (which contains amino acids 1-250), and the AML1/ETO fusion protein (which contains AML1A amino acids 1-177) to stimulate transcription from the GM-CSF promoter, we performed co-transfection experiments in T cells using a human GM-CSF promoter-CAT reporter gene plasmid and expression vectors that contain the cDNAs for one of the above proteins. Our data demonstrate that AML1B, but not AML1A or AML1/ETO transactivates the GM-CSF promoter, requiring the TGTGGT sequence contained between base pairs -68 and -53. Furthermore, we show that AML1/ETO, but not AML1A, inhibits the ability of AML1B to stimulate CAT expression. Electrophoretic mobility shift assays demonstrated the specific binding of AML1 proteins to the GM-CSF promoter TGTGGT sequence, which does not require GM-CSF sequences immediately upstream of this binding site. Our data support a role for AML1B as a transcriptional activator and establish that the AML1/ETO fusion protein can act as a dominant negative protein on the human GM-CSF promoter. Although AML1/ETO does not stimulate the transcription of GM-CSF, it may function by inhibiting the normal activity of AML1B in AML cells with the t(8;21) translocation.

MeSH Terms (15)

Base Sequence Cell Line Core Binding Factor Alpha 2 Subunit DNA-Binding Proteins Granulocyte-Macrophage Colony-Stimulating Factor Humans Molecular Sequence Data Neoplasm Proteins Promoter Regions, Genetic Proto-Oncogene Proteins Receptors, Antigen, T-Cell, alpha-beta Recombinant Fusion Proteins RUNX1 Translocation Partner 1 Protein Transcriptional Activation Transcription Factors

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