MOLECULAR DIAGNOSIS AND MONITORING OF ACUTE PROMYELOCYTIC LEUKEMIA TREATED WITH RETINOIC ACID

The characteristic balanced 15;17 translocation, t(15;17), of acute pr omyelocytic leukemia (APL) fuses the retinoic acid receptor alpha (RAR alpha) gene on chromosome 17 to PML, a recently described gene of unk nown function, on chromosome 15. It is this fusion gene and consequent fusion protein that is thought to be responsible for both the block i n normal myelocyte differentiation as well as the dramatic in vitro an d in vivo response to the differentiating effects of all-trans retinoi c acid (RA). The t(15;17) also provides a genetic marker for the prese nce of leukemic cells. PML/RAR alpha fusion mRNA's can be detected by a reverse transcription polymerase chain reaction (RT-PCR) assay. Usin g this assay, at least three distinct patterns, differing in the 3' re gion of the PML breakpoint, can be identified. The detection of abnorm al mRNA's by the RT-PCR assay has proven to be an important aid in the diagnosis of APL as well as the best predictor of an initial clinical response to RA. The results of an ongoing, longitudinal evaluation of patients with APL show that the RT-PCR assay may also be a useful ind icator of minimal residual disease (MRD). Negative RT-PCR assays follo wing completion of all therapy are associated with prolonged disease f ree survival, whereas persistence or return of a positive test is high ly correlated with subsequent relapse. Further studies will determine whether patients who test positive may benefit from the introduction o f additional anti-leukemic therapy.