ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO.
A 117 bp fragment of the human ELA2 promoter has been characterized that can act as a minimal promoter for the expression of neutrophil elastase. Chromatin immunoprecipitation and siRNAs revealed that expression of ELA2 is regulated by the acute myeloid human leukemia 1 protein (AML1), C/EBPalpha, PU.1 and c-Myb transcription factors. ELA2 has also been investigated as a possible target of the leukemic fusion protein AML1-ETO resulting from the t(8;21) chromosomal translocation. AML1-ETO, like AML1, binds the ELA2 promoter in the myeloid cell lines Kasumi-1 and U937, but unexpectedly fails to significantly alter expression of ELA2. Although AML1-ETO downregulates the expression of C/EBPalpha, changes in C/EBPalpha expression do not correlate with changes in the expression of ELA2. Our observations indicate that AML1-ETO may not be a constitutive repressor of gene expression in every case in which it can associate with DNA, either on its own or in conjunction with C/EBPalpha. Since neither ETO nor AML1-ETO are typically expressed in hematopoietic progenitors, we hypothesize that it is the interactions between AML1-ETO and regulatory cofactors in disease-state cells that alter gene expression programs during hematopoiesis. These protein-protein interactions may not require simultaneous DNA binding by AML1-ETO for the deleterious effects of the fusion protein to be realized.
Lausen
J
J
Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY 10021, USA.
Liu
S
S
Fliegauf
M
M
Lübbert
M
M
Werner
M H
MH
D000208:Acute Disease; D047369:Chromatin Immunoprecipitation; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; D012697:Serine Endopeptidases; C117309:pancreatic elastase II