ACCELERATED EXON SKIPPING OF IRF-1 MESSENGER-RNA IN HUMAN MYELODYSPLASIA LEUKEMIA - A POSSIBLE MECHANISM OF TUMOR-SUPPRESSOR INACTIVATION/

The transcription factor IRF-1 has been shown to function as a tumor s uppressor. Here we report that a significant proportion of the IRF-1 m RNA detected in normal human hematopoietic cells and cultured cell lin es lacks exon 2 (containing the AUG initiation codon) and 3 as a resul t of exon skipping. Surprisingly, when we examined the bone marrow and peripheral mononuclear cells from patients with myelodysplastic syndr ome (MDS) or leukemia secondary to MDS, we could still detect the exon -skipped form but little or none of the intact IRF-1 mRNA. This appear s to be the result of accelerated exon skipping since we could find no mutations within the exons and splicing junctions from these patients . The exon-skipped form of IRF-1 lacking exons 2 and 3 displayed neith er DNA binding nor tumor suppressive activities. Thus this accelerated exon skipping may cause the inactivation of IRF-1 and thereby contrib ute to the development of human hematopoietic malignancies.