Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARa and PLZF-RARa oncoproteins

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations always involving the RARa gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes) in t(15;17) or t(11;17), respectively. APL in patients harboring t(15;17) responds well to retinoic acid (RA) treatment and chemotherapy, whereas t(11;17) APL responds poorly to both treatments, thus defining a distinct syndrome. Here, we show that RA, As2O3, and RA 1 As2O3 prolonged survival in either leukemic PML-RARa transgenic mice or nude mice transplanted with PMLRARa leukemic cells. RA 1 As2O3 prolonged survival compared with treatment with either drug alone. In contrast, neither in PLZF-RARa transgenic mice nor in nude mice transplanted with PLZF-RARa cells did any of the three regimens induce complete disease remission. Unexpectedly, therapeutic doses of RA and RA