EXON SCRAMBLING OF MLL TRANSCRIPTS OCCUR COMMONLY AND MIMIC PARTIAL GENOMIC DUPLICATION OF THE GENE

The MLL gene is frequently rearranged in acute human leukemia of both the myeloid and lymphoid lineages. Using a sensitive reverse transcrip tase-polymerase chain reaction (RT-PCR) assay, we identified several a bnormally spliced transcripts in which MLL exons were joined in an ord er different from the genomic orientation (scrambled exons). Mis-splic ing of MILL was present in both normal and malignant tissues. Although the majority of these scrambled transcripts were joined accurately at consensus splice sites, there were several examples in which the junc tions of exons spliced in aberrant order were at non-consensus sites. A number of features differentiate mis-splicing of MLL from the previo usly described cases of scrambled exons and circular RNAs. Some scramb led transcripts appear to be present in the polyadenylated fraction of RNA. No correlation of exon scrambling with exon skipping was found, and there was no particular tendency for the exons involved to be near large introns. Our data show that splicing of MLL is extremely comple x. The presence of scrambled transcripts in both normal and leukemic c ells, indistinguishable from transcripts resulting from genomic MLL re arrangements, precludes the use of nested RT-PCR as a screening method for detection of tandem duplication of MLL. (C) 1998 Elsevier Science B.V.