Proceedings of the National Academy of Sciences. Developmental stage-specific regulation of Xenopus tRNA genes by an upstream promoter element. The primate specific Alu elements are abundant DNA sequences which were amplified in retroposon fashion and reinserted throughout the genome during the preceding 50 million years. These elements have evolved to contain functional binding sites for retinoic acid and thyroid hormone receptors, ligand-activated transcription factors known to play important roles in the control of cell proliferation and differentiation. These receptor binding sites were present in essentially all Alus at the time of insertion, as indicated by their presence in the deduced Alu founder gene sequences.
Highest expression occurs at the promyelocyte stage in bone marrow myeloid precursors.
As these precursors mature into neutrophils, monocytes and macrophages, MPO expression declines, while the MPO protein remains stored at high levels in lysosomal vesicles. In response to inflammatory signals, MPO is released to the localized enviroment, whereupon it reacts with chloride to generate hypochlorous acid and other reactive oxygen species. These compounds are microbicidal but also have inadvertant cytotoxic effects. Our findings suggest that MPO-generated free radicals cause DNA damage leading to myeloid leukemia, and cellular damage contributing to multiple sclerosis. Myeloid leukemias represent clonal expansions of myeloid precursors, such as promyelocytes, which have lost the ability to differentiate normally.