Promoter demethylation accompanies reactivation of the HOX11 proto-oncogene in leukemia.
Despite considerable work on the epigenetic control of tumor suppressor genes, little is known about the potential role of promoter CpG demethylation in the activation of oncogenes in lymphoid tumors. The HOX11 proto-oncogene is frequently activated in T-cell acute lymphoblastic leukemia (T-ALL). HOX11 activation can occur in the absence of translocation of the gene to the T-cell receptor locus (Salvati et al., 1995), implying that activation mechanisms must be involved other than the juxtaposition of the gene to adjacent enhancing sequences. We tested whether the methylation status of the proximal promoter was correlated with expression status in T-ALL and found that, in all cases, expression of HOX11 in T-ALL was associated with extensive demethylation of the proximal HOX11 promoter, regardless of whether or not translocation was involved. In contrast, cells that did not express HOX11 showed a more methylated pattern of CpG residues in the proximal promoter. Methylation of this sequence in vitro was sufficient to silence the proximal promoter. We propose a model in which the selection of leukemia clones via a pathway involving HOX11 expression requires the demethylation of its promoter as a prerequisite for additional gene activation mechanisms.
Watt
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PM
TVW Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, West Perth, Australia. paulw@ichr.uwa.edu.au
Kumar
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R
Kees
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D002874:Chromosome Mapping; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D008957:Models, Genetic; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011519:Proto-Oncogenes / Q000235:genetics*; D015533:Transcriptional Activation
D018398:Homeodomain Proteins; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C071250:TLX1 protein, human