THE T(15-17) TRANSLOCATION IN ACUTE PROMYELOCYTIC LEUKEMIA

Retinoic acid (RA) is a vitamine A derivative with striking effects on development and cell differentiation. The identification of three RA receptors (RAR alpha, beta and gamma) as members of the nuclear receptor superfamily led to important insights into the molecular mechanism of action of retinoids. The nuclear receptors, that also include receptors for steroid hormone, vitamine D-3 and thyroid hormone act as ligand-inducible transcription factors and are characterized by the presence of two well conserved DNA- and hormone-binding domains. One of the most intriguing properties of RA is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. We and others have shown that the t(15;17) translocation specifically associated with APL fuses an as yet unidentified gene, named PML, to the retinoic acid receptor a locus. The resulting PML-RAR alpha hybrid protein that retains most of the functional domains of parental proteins exhibits altered transactivating functions when compared to the wild-type receptor; however the biological significance of this property in the transforming phenotype is still obscure. PML, whose function is unknown, belongs to a novel family of nuclear proteins characterized by the presence of a Cys/His-rich motif, named a RING finger, that include RNA-binding proteins, transcription factors and oncoproteins. A dimerization domain within PML is able to mediate the formation of PML-RAR alpha homodimers that can bind to target sequences with distinct DNA binding properties if compared with RAR alpha. Immunofluorescence studies have shown that PML is specifically localized within a discrete subnuclear compartment corresponding to nuclear bodies recognized by patient autoimmune sera. In APL cells, the PML-RAR alpha hybrid that accumulates into abnormal substructures is able to delocalize the natural RAR alpha partner, RXR, as well as some of the protein components of the nuclear bodies. This suggests that PML-RAR alpha could act as a dominant negative oncoprotein by diverting a subset of proteins from their natural sites of action. Interestingly, RA treatment induces a complete relocalization of each of these proteins leading to the proposal that the paradoxical therapeutic effect of RA in promoting myeloid differentiation in APL might be related to its ability to restore a normal subnuclear organization.