Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation.
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), and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes. 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 deletions, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. Here we show that the gene encoding alpha-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 region, 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 alpha-catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q).
Liu
Ting Xi
TX
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.
Becker
Michael W
MW
Jelinek
Jaroslav
J
Wu
Wen-Shu
WS
Deng
Min
M
Mikhalkevich
Natallia
N
Hsu
Karl
K
Bloomfield
Clara D
CD
Stone
Richard M
RM
DeAngelo
Daniel J
DJ
Galinsky
Ilene A
IA
Issa
Jean-Pierre
JP
Clarke
Michael F
MF
Look
A Thomas
AT
D000208:Acute Disease; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000097:blood / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000235:genetics / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D020298:U937 Cells; D051178:alpha Catenin / Q000235:genetics* / Q000378:metabolism
C495273:CTNNA1 protein, human; D006877:Hydroxamic Acids; D051178:alpha Catenin; D049452:Green Fluorescent Proteins; C012589:trichostatin A