Identification and monitoring of atypical PML/RARA fusion transcripts in acute promyelocytic leukemia

Once the diagnostic suspicion of acute promyelocytic leukemia (APL) has been raised, international guidelines recommend prompt initiation of tailored therapy and supportive care, while awaiting for genetic confirmation of the diagnosis, and the identification of the specific PML/RARA isoform by RT‐PCR. Depending on the PML breakpoint, usually located within intron 6, exon 6 or intron 3, different PML/RARA transcript isoforms may be generated, that is, long (bcr1), variant (bcr2) and short (bcr3), respectively. We report here the characterization of three APL cases harboring atypical PML/RARA transcripts, which were not clearly detectable after standard RT‐PCR amplification. In all three cases, clinical, morphological and immunophenotypic features were consistent with APL. Direct sequencing allowed the identification of atypical breakpoints within the PML and RARA genes. We then designed a patient‐specific Q‐RT‐PCR for the atypical transcripts, which allowed for specific quantitative evaluation of MRD during follow‐up. Despite the rarity of APL cases with an atypical PML/RARA fusion, our study indicates that an integrated laboratory approach, employing several diagnostic techniques is crucial to timely diagnose APL. This approach allows prompt initiation of specific targeted treatment and reliable MRD monitoring in atypical APL cases.

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