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Changes in DNA Methylation in Neoplasia: Pathophysiology and Therapeutic Implications

Valeria Santini, MD; Hagop M. Kantarjian, MD; and Jean-Pierre Issa, MD
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From the University of Texas M.D. Anderson Cancer Center, Houston, Texas; and University of Florence, Florence, Italy.

Acknowledgment: The authors thank Maria E. Perez for assistance in preparing the manuscript.

Grant Support: Work in Dr. Issa's laboratory is supported by grants from the National Institutes of Health, The Leukemia and Lymphoma Society of America, and the American Cancer Society.

Requests for Single Reprints: Hagop M. Kantarjian, MD, M.D. Anderson Cancer Center, Leukemia Department, Box 61, 1515 Holcombe Boulevard, Houston, TX 77030.

Current Author Addresses: Dr. Santini: Department of Hematology, University of Florence, Viale Morgagni 85, Florence, Italy.

Drs. Kantarjian and Issa: M.D. Anderson Cancer Center, Leukemia Department, Box 61, 1515 Holcombe Boulevard, Houston, TX 77030.

Ann Intern Med. 2001;134(7):573-586. doi:10.7326/0003-4819-134-7-200104030-00011
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Methylation of DNA is a biochemical modification that can influence gene expression and is involved in inactivating one of the two X chromosomes in women. Evidence that has accumulated in the past 10 years suggests that cancer cells usurp this physiologic mechanism and use it to their benefit by inactivating tumor suppressor genes and related proteins. However, the primary structure of the affected proteins remains intact; reversal of abnormalities in DNA methylation may therefore restore the tumor-suppressive function of these genes and provide a novel approach to cancer therapy. Two demethylating drugs, 5-azacytidine and 5-aza-deoxycytidine, are currently being tested in clinical trials, and several others are in preclinical development. In this article, the biological rationale for targeting aberrant methylation in cancer therapy is reviewed and completed phase I and II trials of this approach, some of which show promise for treatment of hematologic malignancies, are summarized.


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Figure 1.
Structure of cytosine, 5-methylcytosine, and hypomethylating 5-methylcytidine analogues.
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Figure 2.
The maintenance methylation process.Top.3Middle.3MtaseBottom.left5-Azaright

Some (but not all) cytosine-followed-by-guanosine (CpG) sites carry a methyl (CH ) group at the 5′ position of cytosine. Both strands of DNA are methylated (“fully methylated”). Immediately after DNA replication, the newly formed strand is unmethylated (no CH groups), resulting in hemimethylated double-stranded DNA, which rapidly attracts one of several methyltransferase ( ) enzymes. Through the action of methyltransferase enzymes, methyl groups are added symmetrically to hemimethylated CpG sites ( ), resulting in fully methylated DNA. In the presence of cytidine analogues ( ), methyltransferases are depleted, and the process of remethylation after replication is inhibited, leading to DNA that remains hemimethylated ( ). With subsequent rounds of replication in the absence of methyltransferases, DNA becomes progressively more demethylated, until most DNA molecules are completely unmethylated.

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Figure 3.
Effects of methylation and histone deacetylation on gene expression and silencing.topblack boxesovalsarrows(leftmMBPbottomHDACrighttop

Initially ( ), genes ( ) are unmethylated, and the promoter region is occupied by transcription factors ( ) that direct production of messenger RNA ( ). De novo methylation, by itself, has a minimal effect on gene expression ). However, methylated DNA ( ) attracts methyl-binding proteins ( ), such as MeCp2 ( ). These methyl-binding proteins in turn attract a protein complex that contains histone deacetylases ( ). At this point, synthesis of messenger RNA synthesis is inhibited and no functional protein can be made from the gene. Through the action of methyl-binding proteins and histone deacetylases, the DNA structure changes to a compact, “condensed chromatin” configuration ( ), which results in permanent inhibition of messenger RNA and protein production (silencing). Hypomethylating agents can reverse this silenced state and restore messenger RNA and protein expression ( ). Histone deacetylase inhibitors act synergistically with hypomethylating agents to restore functional gene expression.

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