Progressive chromatin repression and promoter methylation of CTNNA1 associated with advanced myeloid malignancies.
Complete loss or deletion of the long arm of chromosome 5 is frequent in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). The putative gene(s) deleted and responsible for the pathogenesis of these poor prognosis hematologic disorders remain controversial. This study is a comprehensive analysis of previously implicated and novel genes for epigenetic inactivation in AML and MDS. In 146 AML cases, methylation of CTNNA1 was frequent, and more common in AML patients with 5q deletion (31%) than those without 5q deletion (14%), whereas no methylation of other 5q genes was observed. In 31 MDS cases, CTNNA1 methylation was only found in high-risk MDS (>or=RAEB2), but not in low-risk MDS (<RAEB2), indicating that CTNNA1 methylation might be important in the transformation of MDS to AML. CTNNA1 expression was lowest in AML/MDS patients with CTNNA1 methylation, although reduced expression was found in some patients without promoter methylation. Repressive chromatin marks (H3K27me3) at the promoter were identified in CTNNA1-repressed AML cell lines and primary leukemias, with the most repressive state correlating with DNA methylation. These results suggest progressive, acquired epigenetic inactivation at CTNNA1, including histone modifications and promoter CpG methylation, as a component of leukemia progression in patients with both 5q- and non-5q- myeloid malignancies.
Ye
Ying
Y
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
McDevitt
Michael A
MA
Guo
Mingzhou
M
Zhang
Wei
W
Galm
Oliver
O
Gore
Steven D
SD
Karp
Judith E
JE
Maciejewski
Jaroslaw P
JP
Kowalski
Jeanne
J
Tsai
Hua-Ling
HL
Gondek
Lukasz P
LP
Tsai
Hsing-Chen
HC
Wang
Xiaofei
X
Hooker
Craig
C
Smith
B Douglas
BD
Carraway
Hetty E
HE
Herman
James G
JG
D015153:Blotting, Western; D002478:Cells, Cultured; D002843:Chromatin / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D019175:DNA Methylation; D005455:Fluorescent Antibody Technique; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051178:alpha Catenin / Q000235:genetics*
C495273:CTNNA1 protein, human; D002843:Chromatin; D012333:RNA, Messenger; D051178:alpha Catenin; D008156:Luciferases