ACUTE PROMYELOCYTIC LEUKEMIA - FROM CLINIC TO MOLECULAR-BIOLOGY

Acute promyelocytic leukemia (APL) is a good model for studying the human malignancies in that up to 90% of APL patients can achieve complete remission (CR) with a differentiation inducer, all-trans retinoic acid (ATRA). APL is also associated with a specific chromosomal translocation t(15;17) which fuses the retinoic acid receptor alpha (RAR alpha) gene with a chromosome 15q locus, PML. Recently the RAR alpha and the PML gene structural alterations in t(15;17) have been characterized. The heterogeneity of the PML rearrangements juxtaposes different PML gene portions to the same set of RAR alpha exons, producing two major PML-RAR alpha fusion mRNA isoforms. A retrotranscriptase/polymerase chain reaction (RT-PCR) analysis of the fusion transcripts has been developed which allows the detection of minimal residual disease during the clinical remission of APL. Molecular study showed PML-RAR alpha can form heterodimers with wild-type PML and RXR. Recently, PML has been shown to be one of the components of a nuclear body, POD. In APL, the normal organization of POD is disrupted by PML-RAR alpha, whereas ATRA treatment in vivo and in vitro can induce a reorganization of this organelle. Cytogenetic and molecular study allowed a variant translocation t(11;17) being recently discovered in a small subset of APL. This time RAR alpha is fused to a new gene, PLZF, on chromosome 11q23. It has been shown that the PLZF-RAR alpha, like PML-RAR alpha, has a ''dominant negative'' effect on the wild-type RAR-RXR. Clinical data obtained from a group of t(11;17) APL patients showed that these respond poorly to ATRA and could be grouped in a special clinical syndrome within APL. The comparison of the biological activities mediated by PML-RAR alpha and PLZF RAR alpha mag give new insights into the pathogenesis as well as the mechanisms of ATRA-induced differentiation in APL.