TY - JOUR
T1 - Progressive chromatin repression and promoter methylation of CTNNA1 associated with advanced myeloid malignancies
AU - Ye, Ying
AU - McDevitt, Michael A.
AU - Guo, Mingzhou
AU - Zhang, Wei
AU - Galm, Oliver
AU - Gore, Steven D.
AU - Karp, Judith E.
AU - Maciejewski, Jaroslaw P.
AU - Kowalski, Jeanne
AU - Tsai, Hua Ling
AU - Gondek, Lukasz P.
AU - Tsai, Hsing Chen
AU - Wang, Xiaofei
AU - Hooker, Craig
AU - Smith, B. Douglas
AU - Carraway, Hetty E.
AU - Herman, James G.
PY - 2009/11/1
Y1 - 2009/11/1
N2 - 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 (≥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.
AB - 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 (≥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.
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U2 - 10.1158/0008-5472.CAN-09-1153
DO - 10.1158/0008-5472.CAN-09-1153
M3 - Article
C2 - 19826047
AN - SCOPUS:70350539558
SN - 0008-5472
VL - 69
SP - 8482
EP - 8490
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -