Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid

Acute promyelocytic leukaemia (APL) with t(11;17)/PLZF-RAR alpha responds poorly to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3), in contrast to APL with t(15;17)/PML-RAR alpha. Molecular studies have shown that histone deacetylase (HDAC) recruited by PLZF-RAR alpha is associated with the ATRA resistance. Here, we analysed in vitro the differentiation of APL cells with t(11;17) using ATRA, As2O3, granulocyte colony-stimulating factor (G-CSF), HDAC inhibitor trichostatin A (TSA), or combinations of these. Although 1 mu M ATRA, which stimulated the differentiation of APL cells with t(15;17), was insufficient to induce differentiation, 3 mu M ATRA induced terminal differentiation into granulocytes. As2O3 alone or in combination with ATRA induced neither differentiation nor apoptosis. However, the combination of TSA and 1 mu M ATRA had a potent differentiating effect, although TSA alone had little effect. The combination of 1 mu M ATRA and G-CSF did not induce differentiation. These results indicate that APL cells with t(11;17) need a higher concentration of ATRA than those with t(15;17) to differentiate and suggest that HDAC inhibitor is a promising differentiation enhancer in APL with t(11;17).