HDAC6 as a target for antileukemic drugs in acute myeloid leukemia

Abstract

Inhibition of histone deacetylases (HDACs) by drugs such as vorinostat or depsipeptide has become treatment strategy under study in acute myeloid leukemia. Most preclinically and clinically investigated HDACi target classes I, II and IV, but only few are selective in inhibiting specific HDACs. Here we analyzed the in vitro antileukemic activity of three novel hydroxamate derivatives, the pan-HDAC-inhibitors ST13, ST34 and the known HDAC6 inhibitor ST80, treating leukemia cell lines HL60, Kasumi-1, NB-4, THP-1, K562, U937, Jurkat as well as primary AML blasts. In cell lines all three compounds exerted a strong growth-inhibitory effect at low micromolar concentrations. ST13 increased acetylation of H3, H4 and α-tubulin, while ST34 preferentially acetylated histones H3 and H4. Interestingly, ST80 preferentially induced α-tubulin acetylation at low micromolar doses, confirming a selective inhibition of HDAC6 by ST80 in leukemic cells. These observations were also confirmed in primary AML blasts cultured ex vivo. Growth-inhibition by ST80 was independent of pre-treatment HDAC6 protein expression and in contrast to ST13 and ST34, ST80 did not result in induction of p21/WAF. Immunofluorescence imaging confirmed that ST80 treatment both increased the abundance and resulted in unilateral local accumulation of acetylated α-tubulin. In conclusion, the three novel HDACi show potent antileukemic activity in myeloid cell lines and primary AML blasts at low micromolar concentrations. Preferential acetylation of α-tubulin implies that ST80 might exert its antileukemic effect not through histone reacetylation but rather through inhibition of HDAC6.