الفهرس 
LIST OF CONTENTSOnly 14 pages are availabe for public view
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Abstract
An individual’s genome, the DNA sequence of base pairs, is fixed for life and is nearly identical in every cell type in the entire body. But not all genes are on all of the time; certain physical marks on DNA strands can accumulate over time and shut off genes that are supposed to be on. Shutting down tumor suppressor genes and the proteins they express can destabilize the cell cycle, prevent programmed cell death, and lead to uncontrolled proliferation, namely, tumors. Epigenetics examines how and why these genes have been shut down and what could be done to restore normal expression.
Epigenetics is concerned about heritable changes in gene expression without alteration of the coding sequence. Epigenetic modification of chromatin includes methylation of genomic DNA as well as post-translational modification of chromatin-associated proteins, in particular, histones. Over the past decade, the study on epigenetic modifications has advanced dramatically, in part owing to the achievement that various enzymes catalyzing these modifications have been identified and characterized. Better understanding of the epigenetic modifications and their role in gene expression, cell growth, differentiation, apoptosis, and patho-physiological processes, such as cancer, will help provide new approaches and tools to prevent or control diseases.
Cancer research has generated a body of evidence that link changes to the genome with the carcinogenic process. These changes and in particular modifications in the DNA methylation machinery, have been hypothesized to serve as excellent candidates for the association between environmental exposure and cancer development. Epigenetic changes have been strongly implicated in every step during tumor development and progression. These discoveries have resulted in an increasingly accepted view that epigenetics play a fundamental role in carcinogenesis.
Epigenetic changes occur frequently during tumor development. The major changes are aberrant DNA methylation and histone modification in chromatin. Both these epigenetic events act in concert to silence the expression of genes that suppress tumorigenesis. The aberrant DNA methylation of some of these target genes can be used for early diagnosis of cancer using MSP. In addition, these epigenetic changes are potential targets for therapeutic intervention using inhibitors of DNA methylation and histone deacetylation. The synergistic activation of tumor suppressor genes and the synergistic in vitro antineoplastic activity by the combination of these epigenetic agents suggest that they have interesting potential for the chemotherapy of cancer.
The manipulation of dysregulated transcription factors responsible for hematopoietic differentiation represents a powerful tool to be harnessed for the differentiation therapy of leukemia, pending development of targeted substances. Compounds that already partly achieved this by influencing the epigenetic landscape in favor of growth control and differentiation are already successfully being used clinically and will be developed further, to reduce their toxicity and improve their efficacy. Aberrations of epigenetic regulation of gene expression are proven to play an important role in many diseases including hematologic disorders. Continued rapid improvements in technology make the study of DNA methylation more accessible and exciting. In the next few years, high throughput methods of genome-wide methylation analysis will be commercialized and become widely available. Drugs modulating epigenetic control on gene expression are now used in many hematologic malignant and premalignant disorders as leukemia and myelodysplasia (as azacitidine, decitabine and vorinostat), others are still in stage of clinical trials. These drugs are usually used in combination with conventional chemotherapy or other epigenetic drugs.