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.
"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. "
[Show abstract][Hide abstract] 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.
Genes Chromosomes and Cancer 06/2009; 48(6):480-9. DOI:10.1002/gcc.20654 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myeloperoxidase (MPO) is a heme-containing peroxidase abundantly expressed in neutrophils and to a lesser extent in monocytes. Enzymatically active MPO, together with hydrogen peroxide and chloride, produces the powerful oxidant hypochlorous acid and is a key contributor to the oxygen-dependent microbicidal activity of phagocytes. In addition, excessive generation of MPO-derived oxidants has been linked to tissue damage in many diseases, especially those characterized by acute or chronic inflammation. It has become increasingly clear that MPO exerts effects that are beyond its oxidative properties. These properties of MPO are, in many cases, independent of its catalytic activity and affect various processes involved in cell signaling and cell-cell interactions and are, as such, capable of modulating inflammatory responses. Given these diverse effects, an increased interest has emerged in the role of MPO and its downstream products in a wide range of inflammatory diseases. In this article, our knowledge pertaining to the biologic role of MPO and its downstream effects and mechanisms of action in health and disease is reviewed and discussed.
[Show abstract][Hide abstract] ABSTRACT: BRCA1 is closely related to the pathogenesis of breast cancer, BRCA1 mRNA is reduced in sporadic breast cancer cells despite the lack of mutations. In the present report, we find that MyoD expression and BRCA1 expression is correlated in sporadic breast tumors, overexpression of MyoD and c-myb stimulates BRCA1 expression, knockdown of MyoD and c-myb attenuates BRCA1 expression and attenuates the ability of BRCA1 to protect cells against hydrogen peroxide. MyoD and c-myb interact with p300 and PCAF, forming activating transcriptional complexes which bind to E-box and c-myb sites on the BRCA1 promoter and activate its transcription by inducing histone acetylation. Regulation of BRCA1 expression by MyoD and c-myb complexes may be part of an integral signaling pathway that determines and explains breast cancer susceptibility. Detection expression status of the various proteins in these complexes may predispose to the onset of sporadic breast cancer.
Breast Cancer Research and Treatment 04/2010; 125(3):699-713. DOI:10.1007/s10549-010-0876-1 · 3.94 Impact Factor
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