AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein.

Melnick A, Carlile GW, McConnell MJ, Polinger A, Hiebert SW, Licht JD
Blood. 2000 96 (12): 3939-47

PMID: 11090081

The AML-1/ETO fusion protein, created by the (8;21) translocation in M2-type acute myelogenous leukemia (AML), is a dominant repressive form of AML-1. This effect is due to the ability of the ETO portion of the protein to recruit co-repressors to promoters of AML-1 target genes. The t(11;17)(q21;q23)-associated acute promyelocytic leukemia creates the promyelocytic leukemia zinc finger PLZFt/RAR alpha fusion protein and, in a similar manner, inhibits RAR alpha target gene expression and myeloid differentiation. PLZF is expressed in hematopoietic progenitors and functions as a growth suppressor by repressing cyclin A2 and other targets. ETO is a corepressor for PLZF and potentiates transcriptional repression by linking PLZF to a histone deacetylase-containing complex. In transiently transfected cells and in a cell line derived from a patient with t(8;21) leukemia, PLZF and AML-1/ETO formed a tight complex. In transient assays, AML-1/ETO blocked transcriptional repression by PLZF, even at substoichiometric levels relative to PLZF. This effect was dependent on the presence of the ETO zinc finger domain, which recruits corepressors, and could not be rescued by overexpression of co-repressors that normally enhance PLZF repression. AML-1/ETO also excluded PLZF from the nuclear matrix and reduced its ability to bind to its cognate DNA-binding site. Finally, ETO interacted with PLZF/RAR alpha and enhanced its ability to repress through the RARE. These data show a link in the transcriptional pathways of M2 and M3 leukemia. (Blood. 2000;96:3939-3947)

MeSH Terms (19)

Binding Sites Cell Line Core Binding Factor Alpha 2 Subunit DNA-Binding Proteins Gene Expression Regulation Humans Kruppel-Like Transcription Factors Leukemia, Myeloid, Acute Leukemia, Promyelocytic, Acute Neoplasm Proteins Nuclear Matrix Oncogene Proteins, Fusion Promyelocytic Leukemia Zinc Finger Protein Protein Binding Proto-Oncogene Proteins Repressor Proteins RUNX1 Translocation Partner 1 Protein Transcription, Genetic Transcription Factors

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