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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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|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
Y. Li, H. Nagai, T. Ohno, M. Yuge, S. Hatano, E. Ito, N. Mori, H. Saito, and T. Kinoshita
Aberrant DNA methylation of p57KIP2 gene in the promoter region in lymphoid malignancies of B-cell phenotype
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100(7):
2572 - 2577.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Garcia, B. Martinez-Delgado, A. Cebrian, A. Martinez, J. Benitez, and C. Rivas
Different Incidence and Pattern of p15INK4b and p16INK4a Promoter Region Hypermethylation in Hodgkin's and CD30-Positive Non-Hodgkin's Lymphomas
Am. J. Pathol.,
September 1, 2002;
161(3):
1007 - 1013.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Garcia-Manero, J. Daniel, T. L. Smith, S. M. Kornblau, M.-S. Lee, H. M. Kantarjian, and J.-P. J. Issa
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8(7):
2217 - 2224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Mertens, S. Wolf, P. Schroeter, C. Schaffner, H. Dohner, S. Stilgenbauer, and P. Lichter
Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia
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May 13, 2002;
99(11):
4116 - 4121.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Worm, A. Aggerholm, and P. Guldberg
In-Tube DNA Methylation Profiling by Fluorescence Melting Curve Analysis
Clin. Chem.,
July 1, 2001;
47(7):
1183 - 1189.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Guillerm, E. Gyan, D. Wolowiec, T. Facon, H. Avet-Loiseau, K. Kuliczkowski, F. Bauters, P. Fenaux, and B. Quesnel
p16INK4a and p15INK4b gene methylations in plasma cells from monoclonal gammopathy of undetermined significance
Blood,
July 1, 2001;
98(1):
244 - 246.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. J. Rush, Z. Dai, D. J. Smiraglia, X. Gao, F. A. Wright, M. Fruhwald, J. F. Costello, W. A. Held, L. Yu, R. Krahe, et al.
Novel methylation targets in de novo acute myeloid leukemia with prevalence of chromosome 11 loci
Blood,
May 15, 2001;
97(10):
3226 - 3233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-i. Mizuno, T. Chijiwa, T. Okamura, K. Akashi, Y. Fukumaki, Y. Niho, and H. Sasaki
Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia
Blood,
March 1, 2001;
97(5):
1172 - 1179.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kawakami, J. Brabender, R. V. Lord, S. Groshen, B. D. Greenwald, M. J. Krasna, J. Yin, A. S. Fleisher, J. M. Abraham, D. G. Beer, et al.
Hypermethylated APC DNA in Plasma and Prognosis of Patients With Esophageal Adenocarcinoma
J Natl Cancer Inst,
November 15, 2000;
92(22):
1805 - 1811.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Patel, C. H. Anna, J. F. Foley, P. S. Stockton, F. L. Tyson, J.C. Barrett, and T. R. Devereux
Hypermethylation of the p16 Ink4a promoter in B6C3F1 mouse primary lung adenocarcinomas and mouse lung cell lines
Carcinogenesis,
September 1, 2000;
21(9):
1691 - 1700.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Aggerholm, P. Hokland, P. Guldberg;, and J. G. Herman
DAP-kinase CpG island methylation in acute myeloid leukemia: methodology versus biology?
Blood,
May 1, 2000;
95(9):
2997 - 2999.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Lu, W.-C. Au, W.-S. Yeow, N. Hageman, and P. M. Pitha
Regulation of the Promoter Activity of Interferon Regulatory Factor-7 Gene. ACTIVATION BY INTERFERON AND SILENCING BY HYPERMETHYLATION
J. Biol. Chem.,
October 6, 2000;
275(41):
31805 - 31812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Galm, M. R. Rountree, K. E. Bachman, K.-W. Jair, S. B. Baylin, and J. G. Herman
Enzymatic Regional Methylation Assay: A Novel Method to Quantify Regional CpG Methylation Density
Genome Res.,
January 1, 2002;
12(1):
153 - 157.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
