Proposed mechanisms of PML exon 6 truncations in V-form APL.

In (A), represented by cases C902, E003, E011, and E801, the PML exon 6 fusion site is 54 bp 5′ of the normal PML exon 6/intron 6 boundary (at nucleotide 1685), but the PML genomic breakpoint is 3′ of nucleotide 1685, either in the distal region of PML exon 6 or in intron 6. The loss of 54 nucleotides from exon 6 occurs as a result of an aberrant splicing event. The cryptic 5′ splice donor site (gtgag) is shown. Only the relevant PML and RARα exons are shown for clarity. In (B), the molecular events responsible for case S386 are diagrammed. The PML genomic break is in exon 6 at nucleotide 1711, and the RARα break is in intron 2 at bp –287 relative to the exon 3 boundary. The processed mRNA contains a 19-nucleotide insertion from RARα intron 2 (underlined) that results from use of a cryptic 5′ splice donor site (gtgat) 19 bp downstream from the breaksite. Genomic sequence that is spliced out is shown in lowercase type. Six novel amino acids and a new junctional amino acid (Ser) are incorporated in the final PML-RARα protein and are shown in bold.