EFFECT OF THE ACUTE PROMYELOCYTIC LEUKEMIA PML RAR-ALPHA PROTEIN ON DIFFERENTIATION AND SURVIVAL OF MYELOID PRECURSORS/

Acute promyelocytic leukaemia is characterized by an expansion of haem atopoietic precursors arrested at the promyelocytic stage (1). The dif ferentiation block can be reversed by retinoic acid, which induces bla st differentiation both in vitro (2) and in vivo (3-4). Acute promyelo cytic leukaemia Is also characterized by a 15:17 chromosome translocat ion (5) with breakpoints within the retinoic acid alpha receptor (RAR alpha) gene on 17 and within the PML gene, that encodes a putative tra nscription factor of unknown function (6-7), on 15 (8-10). As a conseq uence of the translocation a PML/RAR alpha gene is formed. It is trasc riptionally active and encodes a PML/RAR alpha fusion protein detectab le in all APL cases (11-14). We expressed the PML/RAR alpha protein in U937 myeloid precursor cell line and show that they: i) lose the capa city to differentiate under the action of different stimuli (vitamin D -3, transforming growth factor beta 1); ii) acquire enhanced sensitivi ty to retinoic acid; iii) exhibit a higher growth rate that is due to a reduction in apoptotic cell death. These results provide the first e vidence of biological activity of PML/RAR alpha and recapitulate criti cal features of the promyelocytic leukaemia phenotype.