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Progressive Chromatin Repression and Promoter Methylation of CTNNA1 Associated with Advanced Myeloid Malignancies

¹ Cancer Biology Program, ² Division of Hematological Malignancies, ³ Division of Oncology Biostatistics at The Sidney Kimmel Comprehensive Cancer Center, Graduate Programs in ⁴ Pathobiology and ⁵ Cellular and Molecular Medicine, ⁶ Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; ⁷ Medizinische Klinik IV, Universitaetsklinikum Aachen, RWTH Aachen, Aachen, Germany; and ⁸ Experimental Hematology and Hematopoiesis Section and Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio

Requests for reprints: Michael A. McDevitt, Division of Hematology, The Johns Hopkins University School of Medicine, Ross Research Building, Room 1033, 720 Rutland Avenue, Baltimore, MD 21205. Phone: 410-502-6702; Fax: 410-955-0185; E-mail: mmcdevi1{at}jhmi.edu and James G. Herman, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 5M59, Baltimore, MD 21231. Phone: 410-955-8506; Fax: 410-614-9884; E-mail: hermaji{at}jhmi.edu.

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. [Cancer Res 2009;69(21):8482–90]

Key Words: CTNNA1 • Methylation • Progressive silencing • AML transformation