Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia.
DNA methylation is associated with malignant transformation, but limitations imposed by genetic variability, tumor heterogeneity, availability of paired normal tissues and methodologies for global assessment of DNA methylation have limited progress in understanding the extent of epigenetic events in the initiation and progression of human cancer and in identifying genes that undergo methylation during cancer. We developed a mouse model of T/natural killer acute lymphoblastic leukemia that is always preceded by polyclonal lymphocyte expansion to determine how aberrant promoter DNA methylation and consequent gene silencing might be contributing to leukemic transformation. We used restriction landmark genomic scanning with this mouse model of preleukemia reproducibly progressing to leukemia to show that specific genomic methylation is associated with only the leukemic phase and is not random. We also identified Idb4 as a putative tumor-suppressor gene that is methylated in most mouse and human leukemias but in only a minority of other human cancers.
Yu
Li
L
Internal Medicine, Division of Hematology/Oncology, The Ohio State University, Columbus, Ohio 43210, USA.
Liu
Chunhui
C
Vandeusen
Jeff
J
Becknell
Brian
B
Dai
Zunyan
Z
Wu
Yue-Zhong
YZ
Raval
Aparna
A
Liu
Te-Hui
TH
Ding
Wei
W
Mao
Charlene
C
Liu
Shujun
S
Smith
Laura T
LT
Lee
Stephen
S
Rassenti
Laura
L
Marcucci
Guido
G
Byrd
John
J
Caligiuri
Michael A
MA
Plass
Christoph
C
D000818:Animals; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D051796:Inhibitor of Differentiation Proteins; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C086479:Idb4 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D014157:Transcription Factors