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Related Collections Neoplasia Oncogenes and Tumor Suppressors Related Letters in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 October 2002, Vol. 100, No. 8, pp. 2957-2964 NEOPLASIA Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment Michael Daskalakis, Tudung T. Nguyen, Carvell Nguyen, Per Guldberg, Gabriele Köhler, Pierre Wijermans, Peter A. Jones, and Michael Lübbert From the Department of Hematology, University of Freiburg Medical Center, Freiburg, Germany; the Department of Hematology, Leyenburg Hospital, The Hague, The Netherlands; the Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark; the Departments of Pathology, University of Freiburg, Germany, and the University Hospital of Münster, Germany; and the Norris Cancer Center, University of Southern California, Los Angeles. p16 and p15, 2 inhibitors of cyclin-dependent kinases, are frequently hypermethylated in hematologic neoplasias. Decitabine, or 5-Aza-2'-deoxycytidine, reverts hypermethylation of these genes in vitro, and low-dose decitabine treatment improves cytopenias and blast excess in ~50% of patients with high-risk myelodysplastic syndrome (MDS). We examined p15 and p16 methylation status in bone marrow mononuclear cells from patients with high-risk MDS during treatment with decitabine, using a methylation-sensitive primer extension assay (Ms-SNuPE) to quantitate methylation, and denaturing gradient gel electrophoresis (DGGE) and bisulfite-DNA sequencing to distinguish individually methylated alleles. p15 expression was serially examined in bone marrow biopsies by immunohistochemistry. Hypermethylation in the 5' p15 gene region was detected in 15 of 23 patients (65%), whereas the 5' p16 region was unmethylated in all patients. Among 12 patients with hypermethylation sequentially analyzed after at least one course of decitabine treatment, a decrease in p15 methylation occurred in 9 and was associated with clinical response. DGGE and sequence analyses were indicative of hypomethylation induction at individual alleles. Immunohistochemical staining for p15 protein in bone marrow biopsies from 8 patients with p15 hypermethylation revealed low or absent expression in 4 patients, which was induced to normal levels during decitabine treatment. In conclusion, frequent, selective p15 hypermethylation was reversed in responding MDS patients following treatment with a methylation inhibitor. The emergence of partially demethylated epigenotypes and re-establishment of normal p15 protein expression following the initial decitabine courses implicate pharmacologic demethylation as a possible mechanism resulting in hematologic response in MDS. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letters in Blood Online: On the use of DNA methylation inhibitors and the reversal of transcriptional silencing Assam El-Osta, Michael Lübbert, Pierre W. Wijermans, Thomas Licht, and Peter A. Jones Blood 2003 101: 1656-1657. 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