Data from Progressive Chromatin Repression and Promoter Methylation of <i>CTNNA1</i> Associated with Advanced Myeloid Malignancies

Abstract

<div>Abstract<p>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 <i>CTNNA1</i> 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, <i>CTNNA1</i> methylation was only found in high-risk MDS (≥RAEB2), but not in low-risk MDS (CTNNA1 methylation might be important in the transformation of MDS to AML. <i>CTNNA1</i> expression was lowest in AML/MDS patients with <i>CTNNA1</i> methylation, although reduced expression was found in some patients without promoter methylation. Repressive chromatin marks (H3K27me3) at the promoter were identified in <i>CTNNA1</i>-repressed AML cell lines and primary leukemias, with the most repressive state correlating with DNA methylation. These results suggest progressive, acquired epigenetic inactivation at <i>CTNNA1</i>, including histone modifications and promoter CpG methylation, as a component of leukemia progression in patients with both 5q− and non-5q– myeloid malignancies. [Cancer Res 2009;69(21):8482–90]</p></div>