Promoter demethylation accompanies reactivation of the HOXII proto-oncogene in leukemia

Despite considerable work on the epigenetic control of tumor suppressor gen es, little is known about the potential role of promoter CpG demethylation in the activation of oncogenes in lymphoid tumors. The HOXII proto-oncogene is frequently activated in T-cell acute lymphoblastic leukemia (T-ALL). HO XII activation can occur in the absence of translocation of the gene to the T-cell receptor locus (Salvati et al., 1995), implying that activation mec hanisms must be involved other than the juxtaposition of the gene to adjace nt enhancing sequences. We tested whether the methylation status of the pro ximal promoter was correlated with expression status in T-ALL and found tha t, in all cases, expression of HOXII in T-ALL was associated with extensive demethylation of the proximal HOXII promoter, regardless of whether or not translocation was involved. In contrast, cells that did not express HOXII showed a more methylated pattern of CpG residues in the proximal promoter. Methylation of this sequence in vitro was sufficient to silence the proxima l promoter. We propose a model in which the selection of leukemia clones vi a a pathway involving HOXII expression requires the demethylation of its pr omoter as a prerequisite for additional gene activation mechanisms. (C) 200 0 Wiley-Liss, Inc.