Letter abstract
Nature Medicine 13, 78 - 83 (2006)
Published online: 10 December 2006 | doi:10.1038/nm1512
Chromosome 5q deletion and epigenetic suppression of the gene encoding 
-catenin (CTNNA1) in myeloid cell transformation
Ting Xi Liu1,2,8, Michael W Becker3,8, Jaroslav Jelinek4, Wen-Shu Wu2, Min Deng1,2, Natallia Mikhalkevich3, Karl Hsu2, Clara D Bloomfield5, Richard M Stone6, Daniel J DeAngelo6, Ilene A Galinsky6, Jean-Pierre Issa4, Michael F Clarke7 & A Thomas Look2
Interstitial loss of all or part of the long arm of chromosome 5, or del(5q), is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS, a preleukemic disorder) and acute myeloid leukemia (AML)1, and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes2. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. 3–7), attempts to identify tumor suppressors within this band have been unsuccessful. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions8, 9, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. Here we show that the gene encoding 
-catenin (CTNNA1) is expressed at a much lower level in leukemia-initiating stem cells from individuals with AML or MDS with a 5q deletion than in individuals with MDS or AML lacking a 5q deletion or in normal hematopoietic stem cells. Analysis of HL-60 cells, a myeloid leukemia line with deletion of the 5q31 region10, 11, showed that the CTNNA1 promoter of the retained allele is suppressed by both methylation and histone deacetylation. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. Thus, loss of expression of the -catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q).
- Laboratory of Development and Diseases, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
- Division of Hematology/Oncology, University of Rochester, Rochester, New York 14642, USA.
- University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
- Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, and Cancer and Leukemia Group, University of Chicago, Chicago, Illinois 60606, USA.
- Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
- Institute of Stem Cell Biology and Regenerative Medicine, and Division of Hematology/Oncology, Internal Medicine, Stanford University, Palo Alto, California 94304, USA.
- These authors contributed equally to this work.
Correspondence to: A Thomas Look2 e-mail: thomas_look@dfci.harvard.edu
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