Genomic and molecular switching in relapsed acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by a recurrent translocation between chromosomes 15 and 17, resulting in the fusion of the promyelocytic leukemia gene (PML) to the retinoic acid receptor α gene (RARα). Among APL cases with a PML-RARα rearrangement, chromosome 15 breakpoints fall within three breakpoint cluster regions (bcrs): bcr1 and bcr3 correspond to PML introns 6 and 3, respectively, whereas bcr2 is located within PML exon 6, or very occasionally within PML exon 5. On the contrary, a single RARα breakpoint region occurs within intron 2. A bcr1 breakpoint is reported in approximately 55% of patients and results in an mRNA fusion of PML exon 6 to RARα exon 3, conventionally referred to as the long (L) isoform. A bcr3 breakpoint occurs in approximately 40% of cases and results in an mRNA fusion of PML exon 3 to RARα exon 3, referred to as the short (S) isoform. A bcr2 breakpoint occurs in approximately 5% of patients and usually results in a tripartite mRNA fusion in which part of PML exon 6 is fused to an insert sequence and then to RARα exon 3, where the insert is usually between 3 and 127 base pairs long and has been presumed to be derived from RARα intron 2. Some cases have no inserted nucleotides and instead use a cryptic splice site within PML exon 6 to splice part of this exon in frame to RARα exon 3. Collectively, these transcripts are referred to as the variable (V) isoform. We report an APL case showing a different genomic and molecular rearrangement at relapse from those observed at the onset of disease