The human MLL (mixed-lineage leukemia or myeloid-lymphoid leukemia) gene belongs to the trithorax gene family of which the Drosophila trithorax (trx) gene is known to regulate homeotic genes through alternative RNA splicing. To test if such a splicing mechanism also operates in MLL, we evaluated mRNA transcripts from a large number of normal and malignant human cells, making use of RT-PCR, PCR cloning, DNA sequencing and Northern blot analysis. Our findings indicate that different cell types transcribe MLL mRNA species lacking exons that generally encode putative regulatory domains such as AT hooks (exon 3), repression domain (exon 6), zinc finger motifs (exon 8) and activation domain (exon 18). Such findings suggest that posttranscriptional regulation by alternative RNA splicing may play an important role in MLL gene expression and provides the rationale for a mechanism by which this gene, with multiple functional domains, could produce discrete protein products that may prove critical in the regulation of human homeobox genes.