Inhibin-Alpha Gene Mutations And Mrna Levels In Human Lymphoid And Myeloid Leukemia Cells

The inhibin-alpha gene was identified as a tumor suppressor gene in the gonads and adrenal glands by functional studies using knockout mice. Methylation of CpG sites within the regulatory regions of tumor suppressor gene is frequently associated with their transcriptional silencing. We investigated epigenetic modifications, changes in loss of heterozygosity (LOH), and mutation of the inhibin-alpha gene, and regulation of transcriptional expression in response to inhibitors of DNA methylation (5-aza-2'-deoxycytidine, 5-AzaC) in human lymphoid (Jurkat, Molt-4, Raji, and IM-9) and myeloid (HL-60, Kasumi-1, and K562) leukemia cells. The inhibin-alpha promoter was hypermethylated in lymphoid (Molt-4 and Raji) and myeloid (HL-60 and Kasumi-1) leukemia cells. Inhibin-a gene mutations differed significantly between lymphoid (heterozygote) and myeloid (homozygote) leukemia cells. LOH in the inhibin-alpha gene was detected in lymphoid and myeloid leukemia cells, with the exception of Jurkat cells. Treatment with 5-AzaC, alpha demethylating agent, resulted in increased inhibin-alpha mRNA and protein levels in most of the cell lines. Also, 5-AzaC treatment inhibited cell proliferation and induced apoptosis. Taken together, our results reveal that the inhibin-alpha gene is transcriptionally silenced in human leukemia cells and that reactivation is suppressed by alpha demethylating agent. In addition, mutations in, and expression levels of, the inhibin-alpha gene differed between human lymphoid and myeloid leukemia cells.