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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2445-2451
p15INK4B CpG Island Methylation in Primary
Acute Leukemia Is Heterogeneous and Suggests Density as a Critical
Factor for Transcriptional Silencing
Elizabeth E. Cameron,
Stephen B. Baylin, and
James G. Herman
From The Oncology Center, Department of Medicine and the Predoctoral
Training Program in Human Genetics, The Johns Hopkins University School
of Medicine, Baltimore, MD.
The promoter region of the cyclin-dependent kinase inhibitor
p15INK4B contains a CpG island that is
hypermethylated in many hematologic malignancies. To explore the
relationship between patterns of methylation and gene transcription, we
used bisulfite genomic sequencing to obtain a detailed analysis of
methylation in acute leukemia, leukemia cell lines, and normal
lymphocytes. The entire CpG island region of p15 was largely
devoid of methylation in normal lymphocytes, but methylation of varying
density was found in primary acute leukemia. Methylation density was
generally conserved between the alleles from each sample, but marked
heterogeneity for the specific CpG sites methylated was observed.
Patterns of methylation were compared and expression assessed with
reverse-transcriptase polymerase chain reaction (RT-PCR). The density
of methylation within the CpG island, and not any specific location,
correlates best with transcriptional loss. Leukemias with methylation
of approximately 40% of the CpG dinucleotides on each allele had complete gene silencing, with variable, but diminished expression with
less dense CpG island methylation. Our results suggest that the
transcriptional silencing of p15 in conjunction with aberrant hypermethylation is best understood as an evolutionary process that
involves progressively increasing methylation of the entire p15
CpG island.
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