Expression patterns of specific promyelocytic/retinoic acid receptor-alpha transcripts in patients with acute...

Several additional promyelocytic/retinoic acid receptor-alpha (PML/RARalpha) transcripts besides bcr1, bcr2, and bcr3 have been identified in patients with acute promyelocytic leukemia (APL). However, the expression levels of these specific isoforms and their clinical relevance have not been studied to date. The real-time quantitative polymerase chain reaction was established to detect each specific isoform of PML/RARalpha transcripts (bcr1/2, P46R3, P4R3, bcr3, and P2R3) in 46 APL patients. Whereas P46R3 and P4R3 isoforms were concurrently expressed in both bcr1- and bcr2-positive patients, P2R3 isoform was expressed only in bcr3-positive patients. A total of 13 patients had lower expression of bcr1/2 (median 11.60%, 0.86-108.51%) than that of P46R3 (median 14.26%, 6.03-222.91%; P = 0.001). The expression level of P4R3 (median 19.10%, 0.71-266.19%) was lower than the sum of bcr1/2 and P46R3 (median 37.94%, 9.62-403.51%) in all cases (P < 0.001). All 16 cases with bcr3 had concurrent low expression of P2R3 (P < 0.001). Structural analysis revealed that both P4R3 and P2R3 splicing resulting in the generation of a premature termination codon, which was recognized by nonsense-mediated decay (NMD). We suggest that alternative splicing of PML/RARalpha transcripts might be involved in NMD and each isoform should be quantified to further understand the pathogenesis of APL, stratify the risk of relapse, and monitor minimal residual disease.