We have shown previously that genes activated by the immunoglobulin heavy chain (IgH) enhancer or promoter in mouse myeloma cells are extinguished upon fusion of the myeloma with a mouse T cell lymphoma. Here we show that the conserved octamer sequence shared by the IgH enhancer and promoter, when multimerized to form a tissue-specific enhancer, can also render a gene extinguishable under the same experimental conditions. Extinction, however, is not correlated with either absence of the tissue-specific transcription factor OTF-2 or loss of its ability to bind the octamer sequence. It was also found that extinction mediated by the IgH enhancer is dominant to transcriptional activation by the SV40 enhancer. We propose, therefore, that the T cell-negative regulator responsible for IgH gene extinction does not simply prevent IgH enhancer activation but interferes with gene expression more directly, perhaps by disrupting the transcription complex established as a result of tissue-specific enhancer activation.