MLL Gene Expression through Alternative RNA Splicing in Hematopoietic Lineage Specific Cells

Abstract

The human MLL gene belongs to the trithorax gene family of which the Drosophila rrirhorax ((-.v) gene is known to regulate homeotic genes through alternative RNA splicing. MLL gene rearrangement or tandem duplication is known to be associated with subsequent development of leukemia and solid tumor in recent year. MLL rearrangement or tandem duplication results in the alteration of gene dosage of each putative regulatory domain of MLL gene. As a posttranscriptional gene expression, an alternative RNA splicing is a mechanism to produce a diverse number of protein isoforms from a single gene by splicing out of intron sequence as well as certain exons which may encode an important regulatory domain. To test if such splicing mechanism operates in MLL during hematopoietic process, mRNA transcripts from human hematopoietic lineage specific cells were evaluated, making use of the reverse transcriptase polymerase chain reaction technique (RT-PCR), PCR cloning and DNA sequencing . It was indicated that cells from different lineage transcribe MLL mRNA species with spliced 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 which in turn may regulate complex process of normal hematopoiesis.