Cellular response to all-trans retinoic acid (ATRA) of acute promyelocytic leukemia (APL) with patient-derived mutant PML-retinoic acid receptor-α (PML-RARα) was investigated using an APL cell line, UF-1, carrying Arg611Trp mutation in PML-RARα. Although the mutant protein showed a decreased ligand-dependent transcriptional activity and retained a dominant-negative effect on normal RARα, UF-1 cells underwent growth inhibition, maturation and apoptosis in response to ATRA at 1 μM, but not ≤100 nM, after 4 days of treatment with ATRA. Moreover, in the presence of 1 μM ATRA, approximately 50% of UF-1 cells expressing annexin V, an early-apoptotic marker, was negative for CD11b and showed immature morphology. These findings suggest that UF-1 cells, despite expressing mutant PML-RARα protein, can be induced by ATRA to undergo differentiation and apoptosis through RA-inducible mechanism(s), in which a proportion of apoptosis may occur independent of terminal differentiation. This unique cell line may be useful for investigating the pathogenesis of ATRA resistance and the mechanism of ATRA-induced apoptosis in APL.
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