C/EBP and C-Myb sites are important for the functional activity of the human myeloperoxidase upstream enhancer

Pathology and Laboratory Medicine Service, Veterans Affairs Medical Center, Decatur, GA 30033, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/2008; 371(2):309-14. DOI: 10.1016/j.bbrc.2008.04.065
Source: PubMed


Myeloperoxidase (MPO), an enzyme active against bacterial and fungal infections, is expressed specifically in myeloblasts and promyelocytes and minimal in other cell types. We recently identified and partially characterized an upstream enhancer located between -4100 and -3844 bp of the MPO gene. We showed that an AML1 site contributes to enhancer activity and specificity. We now demonstrate three additional footprints within the MPO enhancer and provide evidence that C/EBP and c-Myb sites contribute to its functional, tissue-specific activity. This distal enhancer appears to play an important role in the control of MPO transcription during differentiation of myeloid cells.

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    • "The MPO promoter/enhancer region has been extensively studied and contains multiple enhancers over a 5 kb interval including a granulocyte colony stimulating factor response element (GRE; Orita et al., 1997), two binding sites for AML1 (Austin et al., 1998; Yao et al., 2008) and sites for C/EBP and c-Myb (Yao et al., 2008). On the derivative chromosome 17 the upstream enhancers (but not the basal promoter) are translocated 2 kb 5′ of the gene ZNF342 with SYBR green and TaqMan quantitative RT-PCR both demonstrating that ZNF342 is highly overexpressed in the t(17;19) sample. "
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    ABSTRACT: We report a novel translocation t(17;19)(q22;q13.32) found in 100% of blast cells from a pediatric acute myeloid leukemia (AML) patient. Fluorescence in situ hybridization and vectorette polymerase chain reaction were used to precisely map the chromosomal breakpoint located on the derivative chromosome 17 at 352 bp 5' of MPO, encoding myeloperoxidase a highly expressed protein in myeloid cells, and 2,085 bp 5' of ZNF342 on 19q, encoding a transcription factor expressed in human stem cells and previously implicated in mouse models of leukemia. Analysis of RNA levels from the patient sample revealed significant overexpression of ZNF342, potentially contributing to AML formation. This is the first report of a translocation in myeloid leukemia occurring only in the promoter/enhancer regions of the two genes involved, similar to translocations commonly found in lymphoid malignancies. Analysis of ZNF342 protein levels in a large dataset of leukemia samples by reverse phase protein array showed that higher levels of ZNF342 expression in acute lymphoblastic leukemia was associated with poorer outcome (P = 0.033). In the myeloid leukemia samples with the highest ZNF342 expression, there was overrepresentation of FLT3 internal tandem duplication (P = 0.0016) and AML subtype M7 (P = 0.0002). Thus, overexpression of ZNF342 by translocation or other mechanisms contributes to leukemia biology in multiple hematopoietic compartments.
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