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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.
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