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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Epigenomic Changes during Leukemia Cell Differentiation: Analysis of Histone Acetylation and Cytosine Methylation Using CpG Island Microarrays

Bone Marrow Transplant Program, Arizona Cancer Center (M.N., N.H., M.M.O., R.B.I., J.L.M.-R., A.F.L., B.W.F.), Department of Pharmacology & Toxicology (B.W.F.), and ARL Biotechnology Computing Facility (M.L.N., S.J.M., N.C.M.), University of Arizona, Tucson, Arizona

Dysregulation of epigenetic control is an important participant in carcinogenesis. The PML/RAR translocation in acute promyelocytic leukemia (APL) is an example where the resultant fusion protein recruits histone deacetylase complexes to target genes resulting in their inappropriate transcriptional repression. All-trans-retinoic acid (ATRA) acts as a ligand that relieves this repression and produces an epigenetic transcriptional reprogramming of the cancer cell. CpG island microarrays were used to analyze the DNA methylation and histone acetylation state of the human APL cell line NB4 before and after differentiation with ATRA as well as normal peripheral blood mononuclear cells (PBMC). Over 70 CpG islands within 1 kb of transcription start of a known gene are aberrantly methylated in NB4 cells compared with PBMC; however, no changes in cytosine methylation were detected following ATRA-induced differentiation. With respect to histone H4 acetylation, over 100 single-copy CpG islands within 1 kb of transcription start of a known human gene became hyperacetylated following ATRA-induced differentiation. One CpG island was aberrantly methylated in NB4 cells, but became hyperacetylated and was induced following ATRA treatment and was associated with the HoxA1 gene, suggesting it may be a target gene of ATRA in APL. In addition to single-copy sequences, a selective increase in acetylation was detected in satellite DNA when compared with other high-copy sequences, such as Alu or rDNA. In summary, ATRA stimulates complex epigenomic changes during leukemic cell differentiation, and monitoring these changes may help to identify new targets of epigenetic dysfunction.

Address correspondence to: Dr. Bernard W. Futscher, Arizona Cancer Center, 1515 N. Campbell Ave., Tucson AZ 85724-5024. E-mail: bfutscher{at}azcc.arizona.edu

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