Retinoic acid, but not arsenic trioxide, degrades the PLZF/RAR alpha fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient

Primary blasts of a t(11;17)(q23;q21) acute promyelocytic leukaemia (APL) p atient were analysed with respect to retinoic acid (RA) and arsenic trioxid e (As2O3) sensitivity as well as PLZF/RAR alpha status. Although RA induced partial monocytic differentiation ex vivo, but not in vivo, As203 failed t o induce apoptosis in culture, contrasting with t(15;17) APL and arguing ag ainst the clinical use of As203 in t(11;17)(q23;q21) APL. Prior to cell cul ture, PLZF/RAR alpha was found to exactly co-localize with PML onto PML nuc lear bodies. However upon cell culture, it quickly shifted towards microspe ckles, its localization found in transfection experiments. Arsenic trioxide , known to induce aggregation of PML nuclear bodies, left the microspeckled PLZF/RAR alpha localization completely unaffected. RA treatment led to PLZ F/RARa degradation. However, this complete PLZF/RAR alpha degradation was n ot accompanied by differentiation or apoptosis, which could suggest a contr ibution of the reciprocal RAR alpha/PLZF fusion product in leukaemogenesis or the existence of irreversible changes induced by the chimera.