Genomic variability and alternative splicing generate multiple PML/RARα transcripts that encode aberrant PML proteins and PML/RARα isoforms in acute promyelocytic leukaemia

The acute promyelocytic leukaemia (APL) 15;17 translocation generates a PML/RARα chimeric gene which is transcribed as a fusion PML/RARα mRNA. Molecular studies on a large series of APLs revealed great heterogeneity of the PML/RARα transcripts due to: (i) variable breaking of chromosome 15 within three PML breakpoint cluster regions (bcr1, bcr2 and bcr3), (ii) alternative splicings of the PML portion and (iii) alternative usage of two RARα polyadenylation sites. Nucleotide sequence analysis predicted two types of proteins: multiple PML/RARα and aberrant PML. The PML/RARα proteins varied among bcr1, 2 and 3 APL cases and within single cases. The fusion proteins contained variable portions of the PML N terminus joined to the B-F RARα domains; the only PML region retained was the putative DNA binding domain. The aberrant PML proteins lacked the C terminus, which had been replaced by from two to ten amino acid residues from the RARα sequence. Multiple PML/RARα isoforms and aberrant PML proteins were found to coexist in all APLs. These findings indicate that two potential oncogenic proteins are generated by the t(15;17) and suggest that the PML activation pathway is altered in APLs.