Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment

Author:

Daskalakis Michael1,Nguyen Tudung T.1,Nguyen Carvell1,Guldberg Per1,Köhler Gabriele1,Wijermans Pierre1,Jones Peter A.1,Lübbert Michael1

Affiliation:

1. 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.

Abstract

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 p15and 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, selectivep15 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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