RARA Fusion Proteins

The characteristic chromosomal abnormality associated with acute promyelocytic leukemia (APL) is t(15;17)(q22;q21). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the PML::RARA fusion protein.[377] Other more complex chromosomal rearrangements may also lead to a PML::RARA fusion and result in APL.

Patients with a suspected diagnosis of APL can have their diagnosis confirmed by detection of the PML::RARA fusion protein through fluorescence in situ hybridization (FISH), reverse transcriptase–polymerase chain reaction (RT-PCR), or conventional cytogenetics. Quantitative RT-PCR allows identification of the three common transcript variants and is used for monitoring response on treatment and early detection of molecular relapse.[378] In addition, an immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML::RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein.[379-381]

Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA.[382,383] Recognition of these rare variants is important because they differ in their sensitivities to tretinoin and arsenic trioxide.[384]