A comprehensive microarray-based DNA methylation study of 367 hematological neoplasms.
BACKGROUND
Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required.


RESULTS
Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of gene-associated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression.


CONCLUSIONS
We have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes--DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1--that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs.
Martin-Subero
Jose I
JI
Institute of Human Genetics, Christian-Albrechts University, Kiel, Germany. jimartin@idibell.cat
Ammerpohl
Ole
O
Bibikova
Marina
M
Wickham-Garcia
Eliza
E
Agirre
Xabier
X
Alvarez
Sara
S
Brüggemann
Monika
M
Bug
Stefanie
S
Calasanz
Maria J
MJ
Deckert
Martina
M
Dreyling
Martin
M
Du
Ming Q
MQ
Dürig
Jan
J
Dyer
Martin J S
MJ
Fan
Jian-Bing
JB
Gesk
Stefan
S
Hansmann
Martin-Leo
ML
Harder
Lana
L
Hartmann
Sylvia
S
Klapper
Wolfram
W
Küppers
Ralf
R
Montesinos-Rongen
Manuel
M
Nagel
Inga
I
Pott
Christiane
C
Richter
Julia
J
Román-Gómez
José
J
Seifert
Marc
M
Stein
Harald
H
Suela
Javier
J
Trümper
Lorenz
L
Vater
Inga
I
Prosper
Felipe
F
Haferlach
Claudia
C
Cruz Cigudosa
Juan
J
Siebert
Reiner
R
D001402:B-Lymphocytes / Q000378:metabolism; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D020869:Gene Expression Profiling; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000378:metabolism